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class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-jnl-asm-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 data-highwire-cite-ref-tooltip-instance=\u0022highwire_reflinks_tooltip\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003EABSTRACT\u003C\/h2\u003E\u003Cp id=\u0022p-1\u0022\u003EThe master regulator for entry into sporulation in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E is the response regulator Spo0A, which directly governs the expression of about 121 genes. Using cells in which the synthesis of Spo0A was under the control of an inducible promoter or in which production of the regulatory protein was impaired by a promoter mutation, we found that sporulation required a high (threshold) level of Spo0A and that many genes in the regulon differentially responded to high and low doses of the regulator. We distinguished four categories of genes, as follows: (i) those that required a high level of Spo0A to be activated, (ii) those that required a high level of Spo0A to be repressed, (iii) those that were activated at a low level of the regulator, and (iv) those that were repressed at a low dose of the regulator. Genes that required a high dose of Spo0A to be activated were found to have low binding constants for the DNA-binding protein. Some genes that were turned on at a low dose of Spo0A either had a high binding constant for the regulatory protein or were activated by an indirect mechanism involving Spo0A-mediated relief of repression by the repressor protein AbrB. We propose that progressive increases in the level of Spo0A leads to an early phase of transcription in which genes that play auxiliary roles in development, such as cannibalism and biofilm formation, are turned on and a later phase in which genes that play a direct role in sporulation are activated.\u003C\/p\u003E\u003C\/div\u003E\u003Cp id=\u0022p-2\u0022\u003EEntry into the developmental process of spore formation in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E is governed by a master regulatory protein known as Spo0A (\u003Ca id=\u0022xref-ref-1-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003E1\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-21-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E). Spo0A, which is a member of the response regulator family of DNA-binding proteins, is activated at the start of sporulation by a multicomponent phosphorelay consisting of at least three histidine autokinases, KinA, KinB, and KinC, and the phosphorelay proteins Spo0F and Spo0B (\u003Ca id=\u0022xref-ref-6-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-6\u0022\u003E6\u003C\/a\u003E). The kinases phosphorylate Spo0F. Spo0F\u223cP, in turn, transfers the phosphoryl group to Spo0B. Finally, Spo0B\u223cP transfers the phosphoryl group to, and thereby activates, Spo0A. Spo0A is additionally subject to control at the level of its synthesis by a positive feedback loop in which the regulatory protein indirectly stimulates the synthesis of the RNA polymerase sigma factor \u03c3\u003Csup\u003EH\u003C\/sup\u003E, which, in turn, stimulates transcription of the gene for Spo0A as well as the genes for the phosphorelay components KinA and Spo0F (\u003Ca id=\u0022xref-ref-21-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E). The level of phosphorylation of Spo0A\u223cP is also influenced by dedicated phosphatases that remove phosphoryl groups from Spo0F\u223cP (e.g., RapA) and from Spo0A\u223cP itself (Spo0E) (\u003Ca id=\u0022xref-ref-17-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-17\u0022\u003E17\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-24-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-24\u0022\u003E24\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-25-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-25\u0022\u003E25\u003C\/a\u003E). These regulatory mechanisms act in effect as a bistable switch in that under conditions that induce sporulation, only a portion of the cells in the population activate Spo0A, whereas the remainder of the cells do not (\u003Ca id=\u0022xref-ref-9-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-9\u0022\u003E9\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-16-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EOnce activated by phosphorylation, the master regulator binds to a DNA sequence element known as the 0A box (\u003Ca id=\u0022xref-ref-21-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-23-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-33-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-33\u0022\u003E33\u003C\/a\u003E). In certain cases, such as the well-studied example of \u003Cem\u003EabrB\u003C\/em\u003E (\u003Ca id=\u0022xref-ref-14-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-14\u0022\u003E14\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-15-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-15\u0022\u003E15\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-26-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-26\u0022\u003E26\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-27-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-27\u0022\u003E27\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-35-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-35\u0022\u003E35\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-36-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-36\u0022\u003E36\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-39-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-39\u0022\u003E39\u003C\/a\u003E), binding of Spo0A\u223cP to the 0A box results in repression of an otherwise vegetatively expressed gene. In other cases, such as those of the classic sporulation operons \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIE\u003C\/em\u003E, and \u003Cem\u003EspoIIG\u003C\/em\u003E, Spo0A\u223cP acts in conjunction with RNA polymerase containing the housekeeping sigma factor \u03c3\u003Csup\u003EA\u003C\/sup\u003E (as exemplified by \u003Cem\u003EspoIIE\u003C\/em\u003E and \u003Cem\u003EspoIIG\u003C\/em\u003E) or with the alternative sigma factor \u03c3\u003Csup\u003EH\u003C\/sup\u003E (as exemplified by \u003Cem\u003EspoIIA\u003C\/em\u003E) to turn on transcription (\u003Ca id=\u0022xref-ref-28-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-28\u0022\u003E28\u003C\/a\u003E). Thus, Spo0A\u223cP is both a repressor and an activator and is responsible for effecting a switch in the global pattern of gene transcription at the start of sporulation (\u003Ca id=\u0022xref-ref-10-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003E10\u003C\/a\u003E). Although Spo0A is known principally for its role in governing the initiation of sporulation, recent work indicates that Spo0A continues to function at intermediate stages of sporulation, when it accumulates to high levels and directs transcription in the mother cell compartment of the developing sporangium (\u003Ca id=\u0022xref-ref-13-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-13\u0022\u003E13\u003C\/a\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIn recent work, we identified 121 genes that are under the direct control of Spo0A\u223cP (\u003Ca id=\u0022xref-ref-10-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003E10\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-23-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E). These genes are organized as 30 single-gene units and 24 operons (or multigene clusters) and were assigned to the regulon based on a variety of criteria, including transcriptional profiling, chromatin-immunoprecipitation experiments, gel electrophoretic mobility shift assays, and computational approaches. There was, however, reason to suspect that not all members of the regulon are equally responsive to Spo0A. Earlier work based on flow cytometry and the use of a mutant (\u003Cem\u003EkinA\u003C\/em\u003E) that was partially impaired in Spo0A activation indicated that at least one gene (\u003Cem\u003EspoVG\u003C\/em\u003E, which is indirectly under the control of Spo0A via Spo0A-mediated repression of \u003Cem\u003EabrB\u003C\/em\u003E, which encodes a repressor of \u003Cem\u003EspoVG\u003C\/em\u003E [\u003Ca id=\u0022xref-ref-15-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-15\u0022\u003E15\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-36-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-36\u0022\u003E36\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-39-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-39\u0022\u003E39\u003C\/a\u003E] and other genes [\u003Ca id=\u0022xref-ref-27-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-27\u0022\u003E27\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-34-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-34\u0022\u003E34\u003C\/a\u003E]) is activated at a low dose of Spo0A, whereas other genes (e.g., the \u003Cem\u003EspoIIG\u003C\/em\u003E operon) require a high threshold level of Spo0A (\u003Ca id=\u0022xref-ref-9-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-9\u0022\u003E9\u003C\/a\u003E). Motivated by this earlier work, we were interested in revisiting the issue of whether some genes under Spo0A control respond to a low dose of the regulatory protein and others respond to a high dose and to extend this analysis to the entire regulon. Here, we report that many genes in the regulon are differentially responsive to high and low doses of Spo0A, with some genes being activated or repressed at a low dose of the regulatory protein and others requiring a threshold level of Spo0A in order to be turned on or off. Our analysis leads us to propose that different genes are turned on or off at different times as Spo0A levels progressively increase, with genes that do not contribute to sporulation directly, such as genes involved in cannibalism and biofilm formation, being activated earlier and at lower doses of Spo0A than genes that play a direct role in spore formation.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EMATERIALS AND METHODS\u003C\/h2\u003E\u003Cdiv id=\u0022sec-2\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-5\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EPlasmid construction.\u003C\/span\u003EAll plasmid constructions were performed with \u003Cem\u003EEscherichia coli\u003C\/em\u003E DH5\u03b1 by using standard methods. The plasmid used to generate \u003Cem\u003EamyE\u003C\/em\u003E::P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-gfp spc\u003C\/em\u003E (pMF302) was created by ligating the HindIII\u003Cem\u003E-\u003C\/em\u003ESphI PCR fragment containing \u003Cem\u003Egfp\u003C\/em\u003E (oligonucleotide primers omf316 and omf317 and template DNA pMF35 [\u003Ca id=\u0022xref-ref-12-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-12\u0022\u003E12\u003C\/a\u003E]), and pDG1728 (\u003Ca id=\u0022xref-ref-18-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003E18\u003C\/a\u003E) cut with HindIII\u003Cem\u003E-\u003C\/em\u003ESphI. The plasmid used to generate \u003Cem\u003EamyE\u003C\/em\u003E::P\u003Csub\u003E\u003Cem\u003EspoIIA\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-lacZ spc\u003C\/em\u003E (pMF223) was created by ligating the MfeI-HindIII PCR fragment containing \u003Cem\u003EP\u003Csub\u003EspoIIA\u003C\/sub\u003E\u003C\/em\u003E (oligonucleotide primers omf187 and omf188 and template DNA PY79) into pDG1728 between EcoRI and HindIII. The plasmid used to generate \u003Cem\u003EamyE\u003C\/em\u003E::P\u003Csub\u003E\u003Cem\u003EracA\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-lacZ spc\u003C\/em\u003E (pMF225) was created by ligating the EcoRI\u003Cem\u003E-\u003C\/em\u003EHindIII PCR fragment containing \u003Cem\u003EP\u003Csub\u003EracA\u003C\/sub\u003E\u003C\/em\u003E (oligonucleotide primers omf191 and omf192 and template DNA PY79) into pDG1728 between EcoRI and HindIII. The plasmid used to generate \u003Cem\u003EamyE\u003C\/em\u003E::P\u003Csub\u003E\u003Cem\u003EabrB\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-lacZ spc\u003C\/em\u003E (pMF172) was created by ligating the EcoRI\u003Cem\u003E-\u003C\/em\u003EHindIII PCR fragment containing \u003Cem\u003EP\u003Csub\u003EabrB\u003C\/sub\u003E\u003C\/em\u003E (oligonucleotide primers omf114 and omf115 and template DNA PY79) into pDG1728 between EcoRI and HindIII. The plasmid used to generate \u003Cem\u003EamyE\u003C\/em\u003E::P\u003Csub\u003E\u0394V\u003C\/sub\u003E\u003Cem\u003E-Spo0A cm\u003C\/em\u003E (pMF171) was created by ligating the HindIII-BamHI PCR fragment containing P\u003Cem\u003E\u003Csub\u003E\u0394V\u003C\/sub\u003E-Spo0A\u003C\/em\u003E (oligonucleotide primers omf28 and omf111 and template DNA PY79) into pDG1662 (\u003Ca id=\u0022xref-ref-18-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-18\u0022\u003E18\u003C\/a\u003E) between EcoRI and HindIII. The plasmid used to generate \u003Cem\u003EamyE\u003C\/em\u003E::P\u003Csub\u003E\u003Cem\u003Eskf\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-lacZ spc\u003C\/em\u003E (pMF289) was created by ligating the EcoRI\u003Cem\u003E-\u003C\/em\u003EBamHI fragment from plasmid pEG101 (\u003Ca id=\u0022xref-ref-16-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E) containing \u003Cem\u003EP\u003Csub\u003Eskf\u003C\/sub\u003E\u003C\/em\u003E into pDG1728 between EcoRI and BamHI. To construct pEG112 (\u003Cem\u003Esdp\u003C\/em\u003E\u03a9\u003Cem\u003EsdpABC\u003C\/em\u003E::\u003Cem\u003ElacZ cm\u003C\/em\u003E), a 609-bp DNA fragment containing part of \u003Cem\u003EsdpC\u003C\/em\u003E was amplified with the primers YVAYLACECO and YVAYLACBAM. The PCR fragment was digested with EcoRI and BamHI and was cloned into the plasmid pEX44 (\u003Ca id=\u0022xref-ref-16-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E), which was digested with the same restriction enzymes. All plasmids and oligonucleotide primers used for this study are listed in Tables \u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003E1\u003C\/a\u003E and \u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003E2\u003C\/a\u003E, respectively.\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/169441\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/169441\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETABLE 1.\u003C\/span\u003E \u003Cp id=\u0022p-52\u0022 class=\u0022first-child\u0022\u003EBacterial strains and plasmids used in this study\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022T2\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/169507\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/169507\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETABLE 2.\u003C\/span\u003E \u003Cp id=\u0022p-53\u0022 class=\u0022first-child\u0022\u003EOligonucleotide primers used in this study\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-3\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-6\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EStrain construction.\u003C\/span\u003EAll strains used in this study are listed in Table \u003Ca id=\u0022xref-table-wrap-1-2\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003E1\u003C\/a\u003E. The parent strain for all experiments was \u003Cem\u003EB. subtilis\u003C\/em\u003E strain PY79 (\u003Ca id=\u0022xref-ref-38-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-38\u0022\u003E38\u003C\/a\u003E).\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-4\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-7\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003ETranscriptional profiling.\u003C\/span\u003EIn one kind of experiment, we compared the relative levels of transcript accumulation in cells harboring the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E (MF1206) versus cells with a deletion of \u003Cem\u003Espo0A\u003C\/em\u003E (MF476). In the other kind of experiment, we compared transcript levels between cells harboring the P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E (MF1206) construct and cells that were wild type for \u003Cem\u003Espo0A\u003C\/em\u003E (PY79). Cells were induced to sporulate in Sterlini-Mandelstam (SM) medium at 37\u00b0C. Each experiment was carried out twice with cells collected from two independently prepared cultures at 2 h after the start of sporulation. Sample preparation, RNA isolation, labeling, hybridization, and data analyses were performed as previously described (\u003Ca id=\u0022xref-ref-5-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-5\u0022\u003E5\u003C\/a\u003E).\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-5\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-8\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EGeneral methods.\u003C\/span\u003EMedia, culture conditions, preparation of competent cells, preparation of chromosomal and plasmid DNA, assays of sporulation efficiency, and assays of \u03b2-galactosidase activity were as previously described (\u003Ca id=\u0022xref-ref-12-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-12\u0022\u003E12\u003C\/a\u003E).\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-6\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-9\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EGel mobility shift assays.\u003C\/span\u003EGel mobility shift assays were carried out as described previously (\u003Ca id=\u0022xref-ref-14-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-14\u0022\u003E14\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-23-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E). DNA fragments of interest were amplified by PCR from chromosomal DNA from strain PY79 with the primer sets shown in Table \u003Ca id=\u0022xref-table-wrap-2-2\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003E2\u003C\/a\u003E.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-7\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-10\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EFluorescence microscopy.\u003C\/span\u003EFluorescence microscopy was performed as described previously (\u003Ca id=\u0022xref-ref-12-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-12\u0022\u003E12\u003C\/a\u003E).\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-8\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-11\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EImmunoblot analysis.\u003C\/span\u003EImmunoblot analysis was performed as described previously (\u003Ca id=\u0022xref-ref-12-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-12\u0022\u003E12\u003C\/a\u003E). Polyclonal anti-Spo0A (\u003Ca id=\u0022xref-ref-11-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003E11\u003C\/a\u003E) and \u03c3\u003Csup\u003EA\u003C\/sup\u003E antibodies (\u003Ca id=\u0022xref-ref-11-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-11\u0022\u003E11\u003C\/a\u003E) were used for the detection of Spo0A and \u03c3\u003Csup\u003EA\u003C\/sup\u003E, respectively.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-9\u0022\u003E\u003Ch2 class=\u0022\u0022\u003ERESULTS\u003C\/h2\u003E\u003Cdiv id=\u0022sec-10\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-12\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EEfficient sporulation requires a threshold level of Spo0A.\u003C\/span\u003EWe wished to determine whether sporulation is triggered by a threshold level of Spo0A or whether the efficiency of sporulation is simply proportional to the amount of the regulatory protein. To address this issue, we used a strain that had been engineered to produce Spo0A in response to IPTG (isopropyl-\u03b2-\u003Cspan class=\u0022sc\u0022\u003Ed\u003C\/span\u003E-thiogalactopyranoside) by using the IPTG-inducible promoter P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E. Cells were induced to sporulate by suspension in SM medium in the presence of various concentrations of IPTG. The results in Fig. \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003E1\u003C\/a\u003E show that Spo0A levels, as measured by immunoblot analysis, were related linearly to the concentration of IPTG but that sporulation efficiency, as measured by the production of heat-resistant CFU at 24 h, was not. Whereas the level of Spo0A increased approximately in proportion to the concentration of IPTG over the range of 0 to 50 \u03bcM, the efficiency of sporulation abruptly increased over a narrow range, rising from \u0026lt;0.4% of the wild-type level at 20 \u03bcM to 15% of the wild-type level at 30 \u03bcM and 80% of the wild-type level at 40 \u03bcM. In a direct comparison of sporulation to the level of Spo0A, the efficiency of sporulation was 80% of that of the wild type at a Spo0A level that was 80% of that of the wild type but was markedly lower at Spo0A levels that were 65% of the wild-type level or below.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 1.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F1.medium.gif\u0022 width=\u0022440\u0022 height=\u0022288\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 1.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F1.medium.gif\u0022 width=\u0022440\u0022 height=\u0022288\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169338\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 1.\u003C\/span\u003E \u003Cp id=\u0022p-45\u0022 class=\u0022first-child\u0022\u003ESporulation is triggered by a threshold level of Spo0A. The upper panels show immunoblots of extracts from cells in which \u003Cem\u003Espo0A\u003C\/em\u003E was under the control of the IPTG-inducible promoter P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E (MF1256) and from cells of the wild type (PY79). Synthesis of Spo0A was induced in MF1256 by the addition of the indicated concentrations of IPTG just after the cells were suspended in SM medium. Extracts were prepared from cells collected at 2 h after suspension, and proteins were fractionated in a sodium dodecyl sulfate gel containing 16% polyacrylamide. Immunoblot analysis was carried out with polyclonal anti-Spo0A antibodies and polyclonal anti-\u03c3\u003Csup\u003EA\u003C\/sup\u003E antibodies. The anti-\u03c3\u003Csup\u003EA\u003C\/sup\u003E immunoblot served as a control for loading. The lower panel shows the corresponding levels of sporulation and of Spo0A at the indicated concentrations of IPTG. The number of spores per milliliter of culture at 24 h after suspension was measured by the number of heat-resistant (80\u00b0C for 15 min) CFU on agar plates containing Luria broth. Sporulation levels were normalized to the number of spores produced by the wild type (\u223c3 \u00d7 10\u003Csup\u003E8\u003C\/sup\u003E). Spo0A levels from the immunoblot analysis were quantified and normalized to both the levels of \u03c3\u003Csup\u003EA\u003C\/sup\u003E and the levels of Spo0A produced by the wild type.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-13\u0022\u003EAn assumption in the above experiment was that the level of Spo0A was increasing in a similar manner in all cells in the population with the increasing concentrations of IPTG. An alternative possibility was that the P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E promoter responds to IPTG in an all-or-nothing manner, with some cells in the population producing a high level of Spo0A and others producing little or none for any given concentration of the inducer. To distinguish between these possibilities, we created a construct in which the P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E was joined to the gene for the green fluorescent protein (GFP) instead of the gene for Spo0A. We then examined GFP levels by fluorescence microscopy in fields of individual cells at various concentrations of inducer (Fig. \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003E2\u003C\/a\u003E). The results showed that the fluorescence intensity was approximately proportional to the IPTG concentration (the mean value of GFP intensities at a 20 \u03bcM concentration of IPTG was approximately half of that with 50 \u03bcM IPTG) and that, at a particular concentration of IPTG, the level of fluorescence varied from cell to cell by a factor of only about two for the majority (80%) of the cells. We conclude that most cells responded in a similar manner to the dose of IPTG in the medium and, hence, that the level of Spo0A was likely to be largely similar from cell to cell in the population for any given concentration of IPTG.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 2.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F2.medium.gif\u0022 width=\u0022343\u0022 height=\u0022440\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 2.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F2.medium.gif\u0022 width=\u0022343\u0022 height=\u0022440\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169541\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 2.\u003C\/span\u003E \u003Cp id=\u0022p-46\u0022 class=\u0022first-child\u0022\u003EThe response of the P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E promoter to IPTG is moderately uniform from cell to cell. Cells of strain MF2233, which contains a fusion of the gene for GFP to P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E, were treated with 20 and 50 \u03bcM IPTG after suspension in SM medium. The production of GFP was monitored by fluorescence microscopy at hour 2 after suspension. The cells were also visualized by phase contrast microscopy. The lower panels show the relative levels of fluorescence from GFP in individual cells (\u003Cem\u003En\u003C\/em\u003E = 200) at 20 and 50 \u03bcM concentrations of IPTG. The mean values of relative fluorescence at the two concentrations of inducer are indicated with the graphs.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-11\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-14\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EInfluence of the level of Spo0A on the level of expression of various Spo0A-controlled genes.\u003C\/span\u003ENext, we examined the influence of the level of Spo0A on the level of transcription from the promoters for five genes or operons known to be under the positive control of the sporulation regulatory protein (Fig. \u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3\u003C\/a\u003E). These were the promoters for the classic sporulation operons \u003Cem\u003EspoIIA\u003C\/em\u003E and \u003Cem\u003EspoIIG\u003C\/em\u003E and for three recently characterized genes and operons, \u003Cem\u003Eskf\u003C\/em\u003E, \u003Cem\u003Esdp\u003C\/em\u003E, and \u003Cem\u003EracA\u003C\/em\u003E (\u003Ca id=\u0022xref-ref-2-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003E2\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-16-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-28-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-28\u0022\u003E28\u003C\/a\u003E). Transcription was measured by using fusions to \u003Cem\u003ElacZ\u003C\/em\u003E for the genes under study and the P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E-\u003Cem\u003Espo0A\u003C\/em\u003E construct to control the levels of Spo0A synthesis. As a control and for comparison, we also examined \u003Cem\u003EabrB\u003C\/em\u003E, a gene that is repressed by Spo0A but that does not require Spo0A for its transcription (\u003Ca id=\u0022xref-ref-27-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-27\u0022\u003E27\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-34-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-34\u0022\u003E34\u003C\/a\u003E). As expected, \u03b2-galactosidase from an \u003Cem\u003EabrB-lacZ\u003C\/em\u003E fusion accumulated rapidly in the absence of IPTG (i.e., when little or no Spo0A was being synthesized) and at low rates when inducer was present (Fig. \u003Ca id=\u0022xref-fig-3-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3A\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 3.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F3.medium.gif\u0022 width=\u0022440\u0022 height=\u0022260\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 3.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F3.medium.gif\u0022 width=\u0022440\u0022 height=\u0022260\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169442\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 3.\u003C\/span\u003E \u003Cp id=\u0022p-47\u0022 class=\u0022first-child\u0022\u003ETranscription from Spo0A-controlled promoters at various levels of Spo0A. (A) \u03b2-Galactosidase levels were measured in strains harboring the P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E-\u003Cem\u003Espo0A\u003C\/em\u003E construct and \u003Cem\u003ElacZ\u003C\/em\u003E fused to the following promoters: \u003Cem\u003EabrB\u003C\/em\u003E (MF1594), \u003Cem\u003Eskf\u003C\/em\u003E (MF2060), \u003Cem\u003Esdp\u003C\/em\u003E (MF1566), \u003Cem\u003EspoIIA\u003C\/em\u003E (MF1588), \u003Cem\u003EspoIIG\u003C\/em\u003E (MF1532), and \u003Cem\u003EracA\u003C\/em\u003E (MF1649). Cells were treated with 0 (open boxes), 20 (gray boxes), or 50 (filled boxes) \u03bcM concentrations of IPTG after suspension in SM medium. Samples were collected at the indicated times after suspension and assayed for \u03b2-galactosidase activity. For each experiment, the specific activities (Miller units) were normalized to the maximum specific activity observed for each \u003Cem\u003ElacZ\u003C\/em\u003E fusion (typically, 200 U for \u003Cem\u003EabrB\u003C\/em\u003E, \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003Eskf\u003C\/em\u003E, and \u003Cem\u003EracA\u003C\/em\u003E; 500 U for \u003Cem\u003Esdp\u003C\/em\u003E, and 80 U for \u003Cem\u003EspoIIG\u003C\/em\u003E). (B) Shown are immunoblots of extracts prepared from the same cells used for panel A for \u03b2-galactosidase measurements for \u003Cem\u003EspoIIG\u003C\/em\u003E. Immunoblot analysis was carried as described in the legend to Fig. \u003Ca id=\u0022xref-fig-2-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003E2\u003C\/a\u003E. (C) Shown is the quantification of the time course of Spo0A accumulation from the immunoblot analysis shown in panel B, normalized to \u03c3\u003Csup\u003EA\u003C\/sup\u003E levels and then to the maximum level of Spo0A.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-15\u0022\u003EIn keeping with the idea that \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIG\u003C\/em\u003E, \u003Cem\u003Eskf\u003C\/em\u003E, \u003Cem\u003Esdp\u003C\/em\u003E, and \u003Cem\u003EracA\u003C\/em\u003E require Spo0A for their expression, it can be seen that in each case little or no synthesis of \u03b2-galactosidase was observed in the absence of inducer (Fig. \u003Ca id=\u0022xref-fig-3-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3A\u003C\/a\u003E). However, the five genes fell into two categories with respect to how they responded to Spo0A: those that required a high dose of Spo0A for maximal expression and those that were maximally expressed at a low dose of the regulatory protein. Thus, \u03b2-galactosidase from \u003Cem\u003ElacZ\u003C\/em\u003E fusions to \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIG\u003C\/em\u003E, and \u003Cem\u003EracA\u003C\/em\u003E accumulated at low rates when the concentration of IPTG was at 20 \u03bcM and at severalfold-higher rates when the inducer was at 50 \u03bcM (Fig. \u003Ca id=\u0022xref-fig-3-4\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3A\u003C\/a\u003E). It can be seen from the results shown in Fig. \u003Ca id=\u0022xref-fig-3-5\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3B and C\u003C\/a\u003E that the steady-state level of Spo0A at 20 \u03bcM IPTG was approximately 50% of the level seen with the wild type and that at a 50 \u03bcM concentration of inducer the level of Spo0A was equivalent to that of the wild type.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EIn contrast, \u003Cem\u003Eskf\u003C\/em\u003E-\u003Cem\u003ElacZ\u003C\/em\u003E and \u003Cem\u003Esdp\u003C\/em\u003E-\u003Cem\u003ElacZ\u003C\/em\u003E were expressed at maximum levels at IPTG concentrations of either 20 or 50 \u03bcM (Fig. \u003Ca id=\u0022xref-fig-3-6\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3A\u003C\/a\u003E). Interestingly, however, by 2 h after the addition of a high concentration (50 \u03bcM) of inducer, the accumulation of \u03b2-galactosidase from the fusions was curtailed. This observation suggests that transcription from \u003Cem\u003Eskf\u003C\/em\u003E and \u003Cem\u003Esdp\u003C\/em\u003E was repressed as Spo0A accumulated to high levels.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-12\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-17\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EUse of a construct that produces a reduced level of Spo0A to distinguish between high- and low-threshold genes.\u003C\/span\u003EAs an alternative to P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E, we modified the regulatory region for \u003Cem\u003Espo0A\u003C\/em\u003E so as to achieve a reduced level of synthesis of the sporulation regulatory protein. The \u003Cem\u003Espo0A\u003C\/em\u003E gene is transcribed under the direction of \u03c3\u003Csup\u003EA\u003C\/sup\u003E and \u03c3\u003Csup\u003EH\u003C\/sup\u003E from distinct promoters known as P\u003Csub\u003E\u003Cem\u003Ev\u003C\/em\u003E\u003C\/sub\u003E (for vegetative) and P\u003Csub\u003E\u003Cem\u003Es\u003C\/em\u003E\u003C\/sub\u003E (for sporulation), respectively (\u003Ca id=\u0022xref-ref-8-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-8\u0022\u003E8\u003C\/a\u003E). We built a modified \u003Cem\u003Espo0A\u003C\/em\u003E gene that lacked P\u003Csub\u003E\u003Cem\u003Ev\u003C\/em\u003E\u003C\/sub\u003E but retained P\u003Csub\u003E\u003Cem\u003Es\u003C\/em\u003E\u003C\/sub\u003E. When suspended in SM medium, cells harboring the P\u003Csub\u003E\u003Cem\u003Ev\u003C\/em\u003E\u003C\/sub\u003E deletion-mutated gene (P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E) sporulated at an efficiency of 1 to 3% compared to the wild type. Quantitative immunoblot analysis showed that the level of accumulation of Spo0A was about two- to threefold lower in sporulating cells harboring P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E than in sporulating cells containing the wild-type gene (Fig. \u003Ca id=\u0022xref-fig-4-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003E4B and C\u003C\/a\u003E). Thus, cells harboring the P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E construct were locked into producing Spo0A at a modestly reduced level and did so in a manner that was not dependent on the level of inducer in the medium. The observation that cells harboring the P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E construct were strongly impaired in sporulation is in keeping with the conclusion reached above, that efficient sporulation requires a threshold level of Spo0A.\u003C\/p\u003E\u003Cdiv id=\u0022F4\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 4.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F4.medium.gif\u0022 width=\u0022440\u0022 height=\u0022264\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 4.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F4.medium.gif\u0022 width=\u0022440\u0022 height=\u0022264\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F4.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169505\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 4.\u003C\/span\u003E \u003Cp id=\u0022p-48\u0022 class=\u0022first-child\u0022\u003EUse of a promoter-mutated \u003Cem\u003Espo0A\u003C\/em\u003E gene to distinguish between high- and low-threshold genes. (A) \u03b2-Galactosidase activity was measured after suspension in SM medium of cells containing either wild-type \u003Cem\u003Espo0A\u003C\/em\u003E (filled boxes) or the promoter-mutated gene P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E (gray boxes) and \u003Cem\u003ElacZ\u003C\/em\u003E fusions to the following promoters: \u003Cem\u003EabrB\u003C\/em\u003E (\u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E [MF1207], P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E [MF1756]), \u003Cem\u003Eskf\u003C\/em\u003E (\u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E [MF1248], P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E [MF1282]), \u003Cem\u003Esdp\u003C\/em\u003E (\u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E [MF1249], P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E [MF1283]), \u003Cem\u003EspoIIA\u003C\/em\u003E (\u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E [MF1621], P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E [MF1685]), \u003Cem\u003EspoIIG\u003C\/em\u003E (\u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E [MF290], P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E [MF1278]), and \u003Cem\u003EracA\u003C\/em\u003E (\u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E [MF1623], P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E [MF1686]). Specific activities (Miller units) were normalized as described for Fig. \u003Ca id=\u0022xref-fig-3-7\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3\u003C\/a\u003E. (B) Extracts were prepared and subjected to immunoblot analysis as described for Fig. \u003Ca id=\u0022xref-fig-3-8\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003E3\u003C\/a\u003E. (C) Spo0A levels shown in panel B were quantified, normalized to \u03c3\u003Csup\u003EA\u003C\/sup\u003E levels, and then normalized to the maximum level of Spo0A.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-18\u0022\u003ENext, we examined the expression of the \u003Cem\u003ElacZ\u003C\/em\u003E fusions in cells harboring P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E (Fig. \u003Ca id=\u0022xref-fig-4-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003E4A\u003C\/a\u003E). The results show that the pattern of \u03b2-galactosidase accumulation from \u003Cem\u003EabrB-lacZ\u003C\/em\u003E, \u003Cem\u003Eskf-lacZ\u003C\/em\u003E, and \u003Cem\u003Esdp-lacZ\u003C\/em\u003E was similar to that seen with the wild type during the early stages of sporulation (1 to 2 h of sporulation), but reached substantially higher levels than in the wild type later in sporulation. These results are consistent with the idea that \u003Cem\u003Eskf\u003C\/em\u003E and \u003Cem\u003Esdp\u003C\/em\u003E are fully activated at a low concentration of Spo0A but also show that the expression of \u003Cem\u003Eskf\u003C\/em\u003E and \u003Cem\u003Esdp\u003C\/em\u003E is inhibited by Spo0A as the regulatory protein attains progressively higher levels during the course of sporulation.\u003C\/p\u003E\u003Cp id=\u0022p-19\u0022\u003EThat \u003Cem\u003Eskf\u003C\/em\u003E was efficiently expressed at a reduced level of Spo0A was also demonstrated by fluorescence microscopy using a fusion of the gene to \u003Cem\u003Egfp\u003C\/em\u003E (Fig. \u003Ca id=\u0022xref-fig-5-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F5\u0022\u003E5\u003C\/a\u003E). The results show that the \u003Cem\u003Eskf-gfp\u003C\/em\u003E fusion was expressed as strongly in cells harboring P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E as in wild-type cells (although as expected, no expression was seen in cells with a deletion of \u003Cem\u003Espo0A\u003C\/em\u003E). We also noticed that the frequency of polar septa (as observed by the use of the red membrane stain FM4-64) was noticeably lower in cells containing P\u003Cem\u003E\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E than in wild-type cells. This observation is in keeping with the conclusion reached above that the efficiency of sporulation is markedly impaired when the level of Spo0A is reduced below a threshold level and suggests that the defect in sporulation occurs, at least in part, at the stage of asymmetric division.\u003C\/p\u003E\u003Cdiv id=\u0022F5\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F5.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 5.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F5.medium.gif\u0022 width=\u0022440\u0022 height=\u0022265\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 5.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F5.medium.gif\u0022 width=\u0022440\u0022 height=\u0022265\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F5.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169391\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 5.\u003C\/span\u003E \u003Cp id=\u0022p-49\u0022 class=\u0022first-child\u0022\u003EVisualization of transcription from the \u003Cem\u003Eskf\u003C\/em\u003E promoter in cells producing a reduced level of Spo0A. Shown are fluorescence micrographs of cells harboring \u003Cem\u003Egfp\u003C\/em\u003E fused to the \u003Cem\u003Eskf\u003C\/em\u003E promoter fusion and wild-type \u003Cem\u003Espo0A\u003C\/em\u003E (EG297), P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E (MF1317), or a \u003Cem\u003Espo0A\u003C\/em\u003E null mutation \u003Cem\u003Espo0A\u0394\u003C\/em\u003E::\u003Cem\u003Eerm\u003C\/em\u003E (MF1127) at hour 2 after suspension and treated with the membrane stain FM4-64. The upper panels show fluorescence from GFP, and the lower panels show fluorescence from the same cells from FM4-64. Scale bar, 1 \u03bcm.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-20\u0022\u003EThe most striking results were obtained with \u003Cem\u003EspoIIA-lacZ\u003C\/em\u003E, \u003Cem\u003EspoIIG-lacZ\u003C\/em\u003E, and \u003Cem\u003EracA-lacZ\u003C\/em\u003E, which were expressed at only very low levels in cells with the deletion-mutated gene. Evidently, transcription of all three genes requires a threshold level of Spo0A, and its concentration is brought below this threshold by only a modest (two- to threefold) reduction in the level of Spo0A. That such a threshold exists was even more apparent from these results with \u003Cem\u003EP\u003Csub\u003E\u0394v-\u003C\/sub\u003Espo0A\u003C\/em\u003E, for which the cells are locked into producing a level of Spo0A that was modestly reduced from that observed with the P\u003Csub\u003E\u003Cem\u003Espac\u003C\/em\u003E\u003C\/sub\u003E construct.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-13\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-21\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EBinding affinity of Spo0A to the regulatory region for high- and low-threshold genes.\u003C\/span\u003EWe wondered whether high- and low-threshold genes differed in the binding affinities of their regulatory regions for Spo0A. To investigate this possibility, we carried out electrophoretic mobility shift assays using radiolabeled DNAs that contained the binding site for Spo0A and a truncated form of Spo0A that corresponded to its DNA-binding domain, which is located in the C-terminal portion of the protein (\u003Ca id=\u0022xref-ref-23-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E). This truncated protein lacks the region in which phosphorylation takes place and is known to bind DNA in a manner that is not dependent on phosphorylation (\u003Ca id=\u0022xref-ref-30-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-30\u0022\u003E30\u003C\/a\u003E). We therefore assume for the purposes of this analysis that the DNA-binding properties of the truncated protein mimicked those of Spo0A\u223cP. The results indicated apparent \u003Cem\u003EK\u003Csub\u003Ed\u003C\/sub\u003E\u003C\/em\u003E values of 26 nM for \u003Cem\u003Eskf\u003C\/em\u003E, 140 nM for \u003Cem\u003EspoIIA\u003C\/em\u003E, 230 nM for \u003Cem\u003EspoIIE\u003C\/em\u003E, 1,300 nM for \u003Cem\u003Esdp\u003C\/em\u003E, and 1,700 nM for \u003Cem\u003EspoIIG\u003C\/em\u003E (Fig. \u003Ca id=\u0022xref-fig-6-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F6\u0022\u003E6\u003C\/a\u003E). For comparison, the \u003Cem\u003EK\u003Csub\u003Ed\u003C\/sub\u003E\u003C\/em\u003E for \u003Cem\u003EabrB\u003C\/em\u003E was 64 nM. Also, no binding to \u003Cem\u003EspoVG\u003C\/em\u003E, which does not contain a Spo0A-binding site, was detected; \u003Cem\u003EspoVG\u003C\/em\u003E served as the negative control.\u003C\/p\u003E\u003Cdiv id=\u0022F6\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F6.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 6.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F6.medium.gif\u0022 width=\u0022440\u0022 height=\u0022308\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 6.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F6.medium.gif\u0022 width=\u0022440\u0022 height=\u0022308\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F6.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169335\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 6.\u003C\/span\u003E \u003Cp id=\u0022p-50\u0022 class=\u0022first-child\u0022\u003EGel electrophoretic mobility shift analysis of the binding of Spo0A to the regulatory regions of various genes. The regulatory regions of target genes were amplified by PCR with radioactive primers, incubated with the purified DNA-binding domain of Spo0A at the indicated concentrations, and subjected to nondenaturing polyacrylamide gel electrophoresis. \u003Cem\u003EabrB\u003C\/em\u003E is the positive control, and \u003Cem\u003EspoVG\u003C\/em\u003E is the negative control. The data were plotted as fractions of free DNA versus protein concentration to determine \u003Cem\u003EK\u003Csub\u003Ed\u003C\/sub\u003E\u003C\/em\u003E, which was approximately equal to the protein concentration at which half of the free DNA was bound (\u003Ca id=\u0022xref-ref-7-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-7\u0022\u003E7\u003C\/a\u003E). The graph shows the relative binding affinities of Spo0A for the indicated DNAs.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-22\u0022\u003EIn plots of relative binding affinities (Fig. \u003Ca id=\u0022xref-fig-6-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F6\u0022\u003E6\u003C\/a\u003E, lower left), it can be seen that the affinity of \u003Cem\u003Eskf\u003C\/em\u003E for Spo0A was much higher than that for \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIE\u003C\/em\u003E, \u003Cem\u003EspoIIG\u003C\/em\u003E, and \u003Cem\u003Esdp\u003C\/em\u003E (with the affinities of the last two being especially low). This finding is in keeping with our observation that transcription of \u003Cem\u003Eskf\u003C\/em\u003E is switched on at a low cellular level of Spo0A and that \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIE\u003C\/em\u003E, and \u003Cem\u003EspoIIG\u003C\/em\u003E require a high concentration of the sporulation regulatory protein. But how are we to explain the anomalous results with \u003Cem\u003Esdp\u003C\/em\u003E, which was turned on at a low concentration of Spo0A in vivo, but whose binding affinity for Spo0A was almost as low as that for \u003Cem\u003EspoIIG\u003C\/em\u003E?\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-14\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-23\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003ETranscription of \u003Cem\u003Esdp\u003C\/em\u003E is under the negative control of AbrB.\u003C\/span\u003EA possible explanation for the apparent anomaly is that \u003Cem\u003Esdp\u003C\/em\u003E is indirectly activated by Spo0A through relief of repression by the DNA-binding protein AbrB. AbrB is known to repress a variety of genes that are activated at an early stage of sporulation, including \u003Cem\u003EspoVG\u003C\/em\u003E, \u003Cem\u003Espo0E\u003C\/em\u003E, and \u003Cem\u003Espo0H\u003C\/em\u003E (\u003Ca id=\u0022xref-ref-15-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-15\u0022\u003E15\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-27-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-27\u0022\u003E27\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-34-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-34\u0022\u003E34\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-39-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-39\u0022\u003E39\u003C\/a\u003E). AbrB is an unstable protein and its gene is under the negative regulation of Spo0A, which, as we have seen (Fig. \u003Ca id=\u0022xref-fig-6-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F6\u0022\u003E6\u003C\/a\u003E), binds to \u003Cem\u003EabrB\u003C\/em\u003E with relatively high affinity. Thus, as Spo0A levels rise early in sporulation, \u003Cem\u003EabrB\u003C\/em\u003E is repressed, leading to a drop in cellular levels of AbrB and activation of genes under its negative control. To investigate whether \u003Cem\u003Esdp\u003C\/em\u003E is similarly activated by Spo0A-mediated repression of \u003Cem\u003EabrB\u003C\/em\u003E, we examined the effect of an \u003Cem\u003EabrB\u003C\/em\u003E mutation on the expression of \u003Cem\u003Esdp-lacZ\u003C\/em\u003E. The results show that the deletion of \u003Cem\u003EabrB\u003C\/em\u003E resulted in high levels of \u003Cem\u003Esdp-lacZ\u003C\/em\u003E expression and bypassed the dependence of \u003Cem\u003Esdp-lacZ\u003C\/em\u003E expression on \u003Cem\u003Espo0A\u003C\/em\u003E (Fig. \u003Ca id=\u0022xref-fig-7-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F7\u0022\u003E7\u003C\/a\u003E). We note that although \u003Cem\u003Esdp-lacZ\u003C\/em\u003E was activated at a low level of Spo0A, its expression was curtailed at a high level of the regulatory protein (Fig. \u003Ca id=\u0022xref-fig-4-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003E4A\u003C\/a\u003E). We interpret this result to indicate that Spo0A is a repressor of \u003Cem\u003Esdp\u003C\/em\u003E and that when Spo0A accumulates to high levels it is able to adhere to its (relatively weak) binding site, shutting off further transcription of the operon. Thus, as summarized in the model at the bottom of Fig. \u003Ca id=\u0022xref-fig-7-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F7\u0022\u003E7\u003C\/a\u003E, our results are consistent with the view that \u003Cem\u003Esdp\u003C\/em\u003E is both indirectly under the control of Spo0A via repression by AbrB (representing a low-threshold mode of activation) and under its direct negative control through the presence of a weak binding site for Spo0A (representing a high-threshold mode of repression).\u003C\/p\u003E\u003Cdiv id=\u0022F7\u0022 class=\u0022fig pos-float odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F7.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022\u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-265697337\u0022 data-figure-caption=\u0022\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIG. 7.\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F7.medium.gif\u0022 width=\u0022440\u0022 height=\u0022346\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIG. 7.\u0022 src=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F7.medium.gif\u0022 width=\u0022440\u0022 height=\u0022346\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022new-tab first\u0022\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/jb\/187\/4\/1357\/F7.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/169341\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIG. 7.\u003C\/span\u003E \u003Cp id=\u0022p-51\u0022 class=\u0022first-child\u0022\u003EDirect and indirect modes of low-threshold activation by Spo0A. (Top) The graphs are the time course of the accumulation of \u03b2-galactosidase from P\u003Csub\u003E\u003Cem\u003Esdp\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-lacZ\u003C\/em\u003E (left) and P\u003Csub\u003E\u003Cem\u003Eskf\u003C\/em\u003E\u003C\/sub\u003E\u003Cem\u003E-lacZ\u003C\/em\u003E (right) in wild-type (filled diamonds) cells (EG455 for \u003Cem\u003Esdp\u003C\/em\u003E; EG276 for \u003Cem\u003Eskf\u003C\/em\u003E), \u003Cem\u003Espo0A\u003C\/em\u003E mutant cells (open boxes; EG517 for \u003Cem\u003Esdp\u003C\/em\u003E and EG316 for \u003Cem\u003Eskf\u003C\/em\u003E), \u003Cem\u003EabrB\u003C\/em\u003E mutant cells (filled boxes; MF1822 for \u003Cem\u003Esdp\u003C\/em\u003E and MF1895 for \u003Cem\u003Eskf\u003C\/em\u003E), and cells with both \u003Cem\u003Espo0A\u003C\/em\u003E and \u003Cem\u003EabrB\u003C\/em\u003E mutations (filled triangles; MF1830 for \u003Cem\u003Esdp\u003C\/em\u003E and MF1898 for \u003Cem\u003Eskf\u003C\/em\u003E). Samples were collected at the indicated times after the initiation of sporulation and assayed for \u03b2-galactosidase activity. (Bottom) The figure shows models for the regulation of \u003Cem\u003Esdp\u003C\/em\u003E and \u003Cem\u003Eskf\u003C\/em\u003E by Spo0A and AbrB (see the text for details).\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-24\u0022\u003EInterestingly, the results shown in Fig. \u003Ca id=\u0022xref-fig-7-3\u0022 class=\u0022xref-fig\u0022 href=\u0022#F7\u0022\u003E7\u003C\/a\u003E indicate that \u003Cem\u003Eskf\u003C\/em\u003E was both subject to repression by AbrB and under the direct positive control of Spo0A. Thus, the expression of the \u003Cem\u003Eskf-lacZ\u003C\/em\u003E fusion was enhanced in otherwise wild-type cells by a deletion of \u003Cem\u003EabrB\u003C\/em\u003E, but expression was almost entirely prevented by a deletion of \u003Cem\u003Espo0A\u003C\/em\u003E whether or not \u003Cem\u003EabrB\u003C\/em\u003E had been deleted. Thus, as summarized in Fig. \u003Ca id=\u0022xref-fig-7-4\u0022 class=\u0022xref-fig\u0022 href=\u0022#F7\u0022\u003E7\u003C\/a\u003E, low levels of Spo0A activate \u003Cem\u003Eskf\u003C\/em\u003E by two routes: relieving AbrB-mediated repression and direct activation of the \u003Cem\u003Eskf\u003C\/em\u003E promoter.\u003C\/p\u003E\u003Cp id=\u0022p-25\u0022\u003EWe conclude that there are two categories of low-threshold-activated genes, those like \u003Cem\u003Eskf\u003C\/em\u003E, which have a high affinity for Spo0A (and hence require only a low concentration of Spo0A to be activated), and those like \u003Cem\u003Esdp\u003C\/em\u003E, which are under the negative control of AbrB and are indirectly activated at a low concentration of Spo0A through repression of the AbrB gene. In some cases, as exemplified by \u003Cem\u003Eskf\u003C\/em\u003E, the same gene is subject to both mechanisms of low-threshold activation.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-15\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-26\u0022\u003E\u003Cspan class=\u0022inline-l2-heading\u0022\u003EIdentifying other high- and low-threshold genes in the Spo0A regulon.\u003C\/span\u003EIn a previous work, we assigned 121 genes, which are organized as 30 single-gene units and 24 multigene units or operons, to the Spo0A regulon (\u003Ca id=\u0022xref-ref-23-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E). In the present investigation, we sought to carry this analysis further by taking advantage of the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E construct to identify genes whose expression was differentially affected at low or high doses of Spo0A. To do this, we carried out two kinds of gene microarray experiments. In one, we compared the relative levels of transcript accumulation in cells harboring the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E versus cells with a deletion of \u003Cem\u003Espo0A\u003C\/em\u003E. In the other, we compared transcript levels between cells harboring the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E construct and cells that were wild type for \u003Cem\u003Espo0A\u003C\/em\u003E. Our experiments were performed with cells harvested at a time (2 h after suspension in sporulation medium) when Spo0A had reached peak levels in wild-type cells. Because Spo0A is known to influence the expression of many genes that are not under its direct control (e.g., genes under the control of downstream regulatory proteins in the sporulation pathway), we restricted our analysis to genes that had previously been assigned as direct targets of Spo0A (that is, members of the Spo0A regulon).\u003C\/p\u003E\u003Cp id=\u0022p-27\u0022\u003EOur analysis distinguished among four categories of genes. Genes whose expression was at least twofold higher in the wild type than in cells containing the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E construct are referred to as high-threshold-activated genes. Conversely, genes whose expression was at least twofold higher in cells harboring P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E than in the wild type are referred to as high-threshold-repressed genes. Similarly, in the low-threshold category, genes whose expression was at least twofold higher in P\u003Csub\u003E\u003Cem\u003E\u0394v\u003C\/em\u003E\u003C\/sub\u003E-\u003Cem\u003Espo0A\u003C\/em\u003E-containing cells than in a \u003Cem\u003Espo0A\u003C\/em\u003E null mutant were referred to as low-threshold-activated genes whereas genes whose expression was at least twofold higher in \u003Cem\u003Espo0A\u003C\/em\u003E null than in P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E-containing bacteria were referred to as low-threshold-repressed genes. Note that some genes fell into two categories. For example, \u003Cem\u003Esdp\u003C\/em\u003E was activated at a low level of Spo0A (it is a low-threshold-activated gene), but its expression was repressed at high levels of the DNA-binding protein (hence, it is also a high-threshold-repressed gene).\u003C\/p\u003E\u003Cp id=\u0022p-28\u0022\u003ETable \u003Ca id=\u0022xref-table-wrap-3-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T3\u0022\u003E3\u003C\/a\u003E summarizes the results of our analysis for the 53 targets of Spo0A regulation (29 single-gene units plus 24 multigene clusters or operons, leaving aside the unusual case of the late-sporulation-activated gene \u003Cem\u003EcotD\u003C\/em\u003E [\u003Ca id=\u0022xref-ref-23-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E]), which are listed according to the gene that is most proximal to the 0A box in each case. As expected, \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIG\u003C\/em\u003E, \u003Cem\u003EspoIIE\u003C\/em\u003E, and \u003Cem\u003EracA\u003C\/em\u003E fell into the high-threshold-activated category. Three additional genes, \u003Cem\u003EyneE\u003C\/em\u003E, \u003Cem\u003EyttP\u003C\/em\u003E, and \u003Cem\u003EsinI\u003C\/em\u003E, also were in this category, the results being most robust in the case of \u003Cem\u003EyneE\u003C\/em\u003E, a gene of unknown function. Ten genes fell into the category of high-threshold-repressed genes, whose expression was inhibited at a high dose of Spo0A. As expected, and as indicated above, \u003Cem\u003Esdp\u003C\/em\u003E fell into this category. Two other noteworthy members of the high-threshold-repressed category were \u003Cem\u003ErapA\u003C\/em\u003E and \u003Cem\u003EdivIVA\u003C\/em\u003E. The \u003Cem\u003ErapA\u003C\/em\u003E gene encodes a phosphatase that dephosphorylates an intermediate (Spo0F\u223cP) in the phosphorelay (\u003Ca id=\u0022xref-ref-24-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-24\u0022\u003E24\u003C\/a\u003E); hence, its repression by high levels of Spo0A could contribute to maintaining Spo0A activity at a high level. \u003Cem\u003EdivIVA\u003C\/em\u003E is a vegetative gene whose product (together with the product of the high-threshold-activated gene \u003Cem\u003EracA\u003C\/em\u003E) is involved in anchoring chromosome replication origin regions to the cell poles shortly after the start of sporulation (\u003Ca id=\u0022xref-ref-2-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003E2\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-37-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-37\u0022\u003E37\u003C\/a\u003E), among other functions. Because the origin region is released from the pole prior to engulfment, DivIVA is required only early in sporulation, and thus its repression when Spo0A reaches high levels is not inconsistent with the idea that DivIVA acts in only a small window of time.\u003C\/p\u003E\u003Cdiv id=\u0022T3\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/169373\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022view-popup last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/169373\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETABLE 3.\u003C\/span\u003E \u003Cp id=\u0022p-55\u0022 class=\u0022first-child\u0022\u003EHigh- and low-threshold genes in the Spo0A regulon\u003Csup\u003E\u003Cem\u003Ea\u003C\/em\u003E\u003C\/sup\u003E\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-29\u0022\u003EThirteen genes fell into the category of low-threshold-activated genes, that is, genes whose expression was higher in the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E-containing cells than in \u003Cem\u003Espo0A\u003C\/em\u003E mutant cells. As expected, \u003Cem\u003Eskf\u003C\/em\u003E fell into this category, as did the phosphorelay genes, \u003Cem\u003EkinA\u003C\/em\u003E and \u003Cem\u003Espo0F\u003C\/em\u003E, and \u003Cem\u003Espo0A\u003C\/em\u003E itself. Four members of the low-threshold-activated genes were also members of the high-threshold-repressed category. One of the four, as expected and as indicated above, was \u003Cem\u003Esdp\u003C\/em\u003E, with the other three being \u003Cem\u003ErapA\u003C\/em\u003E, \u003Cem\u003EyfmI\u003C\/em\u003E, and \u003Cem\u003EyxbC\u003C\/em\u003E. Expanding on our discussion of \u003Cem\u003ErapA\u003C\/em\u003E (above), we suppose that low doses of Spo0A stimulate synthesis of the Spo0F\u223cP phosphatase and thereby help to prolong the period at which Spo0A activity is at a low level, whereas when Spo0A finally accumulates to a high level, further synthesis of the phosphatase is curtailed to help maintain the regulatory protein at a high-threshold level.\u003C\/p\u003E\u003Cp id=\u0022p-30\u0022\u003EFinally, six genes fell into the low-threshold-repressed category, in which expression was higher in the \u003Cem\u003Espo0A\u003C\/em\u003E mutant than in cells containing the P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E construct. Notable in this category was \u003Cem\u003EabrB\u003C\/em\u003E, whose expression is repressed at a relatively low level of Spo0A. This observation reinforces the view that some of the effects of low doses of Spo0A are exerted indirectly by blocking further synthesis of the unstable AbrB repressor, which we have proposed is the basis for the activation of \u003Cem\u003Esdp\u003C\/em\u003E.\u003C\/p\u003E\u003Cp id=\u0022p-31\u0022\u003EIn toto, 32 genes and operons out of the total list of 53 fell into one of the four categories of high- and low-threshold response, with some genes being assigned to two categories. This left 20 of the Spo0A-regulated targets that did not fall into any of the four categories (leaving aside the case of \u003Cem\u003EyuxH\u003C\/em\u003E, which we discuss below). An inspection of the transcriptional profiling data of Molle et al. (\u003Ca id=\u0022xref-ref-23-7\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E) indicates that many of these 20 genes are cases in which the microarray data revealed a relatively small influence of Spo0A-Sad67 (the activated form of Spo0A used in the experiments of Molle et al.) on transcript levels and, hence, represent weak targets of Spo0A regulation. In other words, the majority of genes in the regulon for which the influence of Spo0A on transcript levels was relatively strong responded to the transcriptional regulator in a manner that was dependent upon its dose.\u003C\/p\u003E\u003Cp id=\u0022p-32\u0022\u003EFinally, we consider the case of \u003Cem\u003EyuxH\u003C\/em\u003E, which we had previously determined was under the negative control of Spo0A (\u003Ca id=\u0022xref-ref-23-8\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E) but which in our present investigation appeared to behave as a high-threshold-activated gene (the transcriptional ratio of transcript accumulation in the wild type versus P\u003Cem\u003E\u003Csub\u003E\u0394v\u003C\/sub\u003E-spo0A\u003C\/em\u003E being 13.3.) A possible explanation for this discrepancy was that the cells used in the present study were wild type for the sporulation regulatory protein \u03c3\u003Csup\u003EE\u003C\/sup\u003E, whereas the experiments of Molle et al. (\u003Ca id=\u0022xref-ref-23-9\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-23\u0022\u003E23\u003C\/a\u003E) were conducted under conditions in which \u03c3\u003Csup\u003EE\u003C\/sup\u003E was absent. Further, adjacent to and in convergent orientation with \u003Cem\u003EyuxH\u003C\/em\u003E is a gene (\u003Cem\u003EyucZ\u003C\/em\u003E) which is under the control of \u03c3\u003Csup\u003EE\u003C\/sup\u003E. Therefore, the strong \u003Cem\u003Espo0A\u003C\/em\u003E\u003Csup\u003E+\u003C\/sup\u003E-dependent signal detected in our microarray analysis might have been an indirect consequence of \u03c3\u003Csup\u003EE\u003C\/sup\u003E-dependent, read-through transcription from \u003Cem\u003EyucZ\u003C\/em\u003E (the microarray was constructed with PCR-amplified open reading frames and hence contained both strands for each gene). We therefore fused \u003Cem\u003ElacZ\u003C\/em\u003E to the promoter for \u003Cem\u003EyuxH\u003C\/em\u003E so that its expression could be studied independently of read-through from \u003Cem\u003EyucZ\u003C\/em\u003E. The results showed that \u003Cem\u003EyuxH-lacZ\u003C\/em\u003E was expressed more strongly in \u003Cem\u003Espo0A\u003C\/em\u003E mutant cells than in the wild type (data not shown) and, hence, that \u003Cem\u003EyuxH\u003C\/em\u003E is indeed under the negative control of Spo0A as reported previously.\u003C\/p\u003E\u003Cp id=\u0022p-33\u0022\u003EIncidental to our analysis, we observed indirect effects of high and low doses of Spo0A on the expression of many additional genes that are not members of the regulon. These data are available as supplemental material (Table S1).\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-16\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EDISCUSSION\u003C\/h2\u003E\u003Cp id=\u0022p-34\u0022\u003EThe principal contribution of this investigation is the finding that many of the genes in the Spo0A regulon respond to the transcription factor in a dose-dependent manner. Indeed, this was true for the large majority of the genes whose transcription was strongly influenced by Spo0A. We assume in our analysis that the amount of Spo0A was proportional to the amount of Spo0A\u223cP, the active form of the response regulator. We were unable to test this assumption experimentally (because of the instability of Spo0A\u223cP), but there is likely to be at least a partial correlation between the level of Spo0A and the level of its phosphorylation as Spo0A is part of a positive feedback loop in which the response regulator directly and indirectly stimulates the expression of genes involved its phosphorylation (\u003Ca id=\u0022xref-ref-21-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-35\u0022\u003EOur analysis distinguished four categories of responses to Spo0A: genes that were activated at a low dose of Spo0A, genes that required a high-threshold level of Spo0A to be activated, genes that were repressed at a low level of Spo0A and, finally, genes that were repressed in a manner that required a high-threshold level of the regulatory protein. We distinguish between direct and indirect mechanisms by which genes respond to low and high doses of Spo0A. One mechanism involves the affinity of the gene in question for Spo0A. Thus, the regulatory region for the \u003Cem\u003Eskf\u003C\/em\u003E operon has a relatively high-affinity binding site for Spo0A, explaining its activation at a low level of the regulatory protein. In contrast, the regulatory regions for the sporulation operons \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIE\u003C\/em\u003E, and \u003Cem\u003EspoIIG\u003C\/em\u003E have relatively weak affinities for Spo0A, which is consistent with the observation that these transcription units require a high level of Spo0A to be switched on. The second mechanism is indirect activation via repression of the gene for the unstable repressor protein AbrB, a well-known global regulator of numerous genes that commence expression at the end of the exponential phase of growth (\u003Ca id=\u0022xref-ref-15-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-15\u0022\u003E15\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-27-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-27\u0022\u003E27\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-34-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-34\u0022\u003E34\u003C\/a\u003E-\u003Ca id=\u0022xref-ref-36-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-36\u0022\u003E36\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-39-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-39\u0022\u003E39\u003C\/a\u003E). Thus, and as we have shown here, the \u003Cem\u003Esdp\u003C\/em\u003E operon is subject to repression by AbrB. At low doses, Spo0A represses \u003Cem\u003EabrB\u003C\/em\u003E, which leads to depletion of the unstable regulatory protein and, hence, relief from AbrB-mediated repression. Indeed, from the point of view of its activation, \u003Cem\u003Esdp\u003C\/em\u003E would not be considered a member of the Spo0A regulon. However, \u003Cem\u003Esdp\u003C\/em\u003E is additionally and directly subject to repression by Spo0A through the presence of a weak binding site for the regulatory protein, which is responsible for shutting off continued transcription of the operon at high doses of Spo0A.\u003C\/p\u003E\u003Cp id=\u0022p-36\u0022\u003EInterestingly, several genes in the regulon are subject to both direct and indirect modes of regulation by Spo0A. Thus, \u003Cem\u003Eskf\u003C\/em\u003E was subject to repression by AbrB, but the expression of the operon was also almost entirely dependent on Spo0A in a manner that was independent of AbrB. That \u003Cem\u003Esdp\u003C\/em\u003E and \u003Cem\u003Eskf\u003C\/em\u003E are subject to negative control by AbrB was also observed by M. Strauch (personal communication), who has also demonstrated the presence of binding sites for the repressor protein in the regulatory regions of both operons.\u003C\/p\u003E\u003Cp id=\u0022p-37\u0022\u003ETwo other examples of genes that are directly and indirectly regulated by Spo0A are the phosphorelay genes \u003Cem\u003EkinA\u003C\/em\u003E and \u003Cem\u003Espo0A\u003C\/em\u003E itself. Both genes have binding sites for Spo0A (\u003Ca id=\u0022xref-ref-21-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E), and biochemical evidence indicates that both are repressed by the response regulator at high concentrations (\u003Ca id=\u0022xref-ref-14-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-14\u0022\u003E14\u003C\/a\u003E). Yet, as shown here, \u003Cem\u003EkinA\u003C\/em\u003E and \u003Cem\u003Espo0A\u003C\/em\u003E fell into the category of low-threshold-activated genes. It is known that both genes are transcribed by \u03c3\u003Csup\u003EH\u003C\/sup\u003E-containing RNA polymerase (\u003Ca id=\u0022xref-ref-14-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-14\u0022\u003E14\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-29-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-29\u0022\u003E29\u003C\/a\u003E). Thus, low-threshold activation of \u003Cem\u003EkinA\u003C\/em\u003E and \u003Cem\u003Espo0A\u003C\/em\u003E is likely to be mediated by the positive feedback loop discussed above, in which Spo0A stimulates \u03c3\u003Csup\u003EH\u003C\/sup\u003E synthesis by relieving AbrB-mediated repression of \u003Cem\u003Espo0H\u003C\/em\u003E (the structural gene for \u03c3\u003Csup\u003EH\u003C\/sup\u003E).\u003C\/p\u003E\u003Cp id=\u0022p-38\u0022\u003EThe case of the \u003Cem\u003ErapA\u003C\/em\u003E gene is of special interest because it is both activated at a low dose of Spo0A and repressed at a high dose. The \u003Cem\u003ErapA\u003C\/em\u003E gene encodes a phosphatase that drains phosphoryl groups from the phosphorelay (specifically from the phosphorelay intermediate Spo0F\u223cP) that is responsible for activating Spo0A (\u003Ca id=\u0022xref-ref-24-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-24\u0022\u003E24\u003C\/a\u003E). As discussed above, the activation of \u003Cem\u003ErapA\u003C\/em\u003E at a low dose of Spo0A would be expected to retard Spo0A levels from rising rapidly and would thus facilitate the persistence of Spo0A at a low concentration. As noted above, Spo0A indirectly stimulates its own transcription by inhibiting the synthesis of AbrB, which is a repressor of the gene for \u03c3\u003Csup\u003EH\u003C\/sup\u003E (\u003Ca id=\u0022xref-ref-21-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-21\u0022\u003E21\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-27-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-27\u0022\u003E27\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-34-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-34\u0022\u003E34\u003C\/a\u003E). The \u03c3\u003Csup\u003EH\u003C\/sup\u003E factor, in turn, is responsible for directing transcription from one of the two promoters that govern the expression of the \u003Cem\u003Espo0A\u003C\/em\u003E gene. Thus, diminished phosphorylation of Spo0A via the action of RapA would limit the rate of Spo0A synthesis. Conversely, repression of \u003Cem\u003ErapA\u003C\/em\u003E at a high dose of Spo0A would curtail further synthesis of the phosphatase. Thus, once Spo0A does eventually reach a high-threshold level, the diminished synthesis of RapA would help ensure that phosphorylation and synthesis of Spo0A continue at a high rate.\u003C\/p\u003E\u003Cp id=\u0022p-39\u0022\u003EWhat is the biological significance of having differential responses to high and low doses of Spo0A? A possible clue comes from the nature of the genes that are turned on at different levels of Spo0A, some of which are directly involved in sporulation and some of which have other functions. Thus, \u003Cem\u003EracA\u003C\/em\u003E, \u003Cem\u003EspoIIA\u003C\/em\u003E, \u003Cem\u003EspoIIE\u003C\/em\u003E, and \u003Cem\u003EspoIIG\u003C\/em\u003E require high levels of Spo0A to be activated and all are directly involved in sporulation. Moreover, and as we have seen, sporulation is itself a high-threshold process, requiring a high level of Spo0A in order to proceed efficiently. In contrast, \u003Cem\u003Eskf\u003C\/em\u003E and \u003Cem\u003Esdp\u003C\/em\u003E are switched on at a low level of Spo0A, in keeping with the idea that the products of these operons are involved in a process that delays cells that have activated Spo0A from becoming committed to sporulation. Conditions of nutrient limitation, which lead to entry into sporulation, typically cause the appearance of two kinds of cells: those that have activated Spo0A and those that have not (\u003Ca id=\u0022xref-ref-9-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-9\u0022\u003E9\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-16-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E). The \u003Cem\u003Eskf\u003C\/em\u003E and \u003Cem\u003Esdp\u003C\/em\u003E operons are responsible for the production of a killing factor and a sporulation-delaying protein that block sibling cells that have not activated Spo0A from entering sporulation. Instead, the sibling cells undergo lysis, thereby providing a source of nutrients for the cells that have activated Spo0A and hence blocking them from progressing further into sporulation. Seen in the light of this cannibalistic process, it makes sense that genes that delay progression into sporulation are activated at a low level of Spo0A and that genes that are directly involved in sporulation require high levels of the regulatory protein to be switched on.\u003C\/p\u003E\u003Cp id=\u0022p-40\u0022\u003EYet another biological process that helps to explain the meaning of high- and low-threshold responses to Spo0A is biofilm formation. Biofilms are multicellular communities of cells, and recent work has shown that cells of \u003Cem\u003EB. subtilis\u003C\/em\u003E are capable of assembling into such communities (\u003Ca id=\u0022xref-ref-3-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E3\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-4-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-4\u0022\u003E4\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-20-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003E20\u003C\/a\u003E). Importantly, in the present context, biofilm formation is dependent upon Spo0A (\u003Ca id=\u0022xref-ref-3-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E3\u003C\/a\u003E, \u003Ca id=\u0022xref-ref-19-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-19\u0022\u003E19\u003C\/a\u003E). One of the targets of Spo0A that is important in biofilm formation is \u003Cem\u003EabrB\u003C\/em\u003E, which is evidently responsible for repressing one or more genes involved in multicellularity (\u003Ca id=\u0022xref-ref-20-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-20\u0022\u003E20\u003C\/a\u003E) and which, as we have seen, is repressed at a low dose of Spo0A. Another potential target of Spo0A in biofilm formation is \u003Cem\u003EsinI\u003C\/em\u003E, whose product is an antagonist of the repressor protein SinR (\u003Ca id=\u0022xref-ref-1-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003E1\u003C\/a\u003E) and whose expression is stimulated by Spo0A (\u003Ca id=\u0022xref-ref-31-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-31\u0022\u003E31\u003C\/a\u003E). Recent work has shown that SinR plays a central role in biofilm formation by controlling the expression of the \u003Cem\u003Eeps\u003C\/em\u003E operon, which is responsible for the production of the exopolysaccharide that is believed to be responsible for binding chains of cells together in the biofilm (\u003Ca id=\u0022xref-ref-22-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-22\u0022\u003E22\u003C\/a\u003E). Thus, the Spo0A-directed expression of \u003Cem\u003EsinI\u003C\/em\u003E would be expected to (indirectly) turn on expression of the \u003Cem\u003Eeps\u003C\/em\u003E operon and thereby promote biofilm formation. Our analysis classified \u003Cem\u003EsinI\u003C\/em\u003E as a high-threshold-activated gene, but inspection of the results in Table \u003Ca id=\u0022xref-table-wrap-3-2\u0022 class=\u0022xref-table\u0022 href=\u0022#T3\u0022\u003E3\u003C\/a\u003E shows that its differential response to high levels of Spo0A was the least robust of that of all of the genes in the category. Conceivably, therefore, transcription of \u003Cem\u003EsinI\u003C\/em\u003E is stimulated at a somewhat lower level of Spo0A than is required to activate sporulation-specific genes. If so, then biofilm formation is a low-threshold response to Spo0A or, at least, a lower dose response than is sporulation. Wild strains of \u003Cem\u003EB. subtilis\u003C\/em\u003E produce particularly robust biofilms with complex architectural features, including fruiting-body-like aerial structures in which spore formation preferentially takes places at the tips (\u003Ca id=\u0022xref-ref-3-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E3\u003C\/a\u003E). Biofilm formation in wild strains can therefore be seen as a prelude to spore formation, with a low level of Spo0A promoting the formation of fruiting bodies and the eventual attainment of high levels of Spo0A-activating genes that mediate the process of spore formation itself.\u003C\/p\u003E\u003Cp id=\u0022p-41\u0022\u003EIn sum, and in an extension of earlier work, our findings lead to the view that cells exist in at least four states with respect to Spo0A, each with its own biological significance. First, activation of Spo0A in response to conditions of nutrient limitation is governed by a bistable switch in which some cells in the population activate the regulatory protein and others do not. Second, cells that have activated Spo0A initially produce the regulatory protein at a low level that is sufficient to activate genes involved in specialized processes, such as cannibalism and biofilm formation, but not spore formation. Indeed, the cannibalism phenomenon depends on the existence of a population of cells that have not activated Spo0A (\u003Ca id=\u0022xref-ref-16-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-16\u0022\u003E16\u003C\/a\u003E). Third, cells that have activated Spo0A enter a state in which the transcription factor accumulates to high levels, thereby unleashing the expression of genes critical for the initial stages of spore formation. Finally, at intermediate stages of sporulation, Spo0A accumulates to very high levels in a cell-specific manner when it promotes gene expression in the mother cell compartment of the sporangium (\u003Ca id=\u0022xref-ref-13-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-13\u0022\u003E13\u003C\/a\u003E).\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section ack\u0022 id=\u0022ack-1\u0022\u003E\u003Ch2\u003EACKNOWLEDGMENTS\u003C\/h2\u003E\u003Cp id=\u0022p-43\u0022\u003EWe thank M. Strauch for communicating unpublished results and M. Strauch, S. Branda, and D. Kearns for helpful comments.\u003C\/p\u003E\u003Cp id=\u0022p-44\u0022\u003EThis work was supported by NIH grant GM18568.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section fn-group\u0022 id=\u0022fn-group-1\u0022\u003E\u003Ch2\u003EFOOTNOTES\u003C\/h2\u003E\u003Cul\u003E\u003Cul class=\u0022history-list\u0022\u003E\u003Cli xmlns:hwp=\u0022http:\/\/schema.highwire.org\/Journal\u0022 class=\u0022received\u0022 hwp:start=\u00222004-10-09\u0022\u003E\u003Cspan class=\u0022received-label\u0022\u003EReceived \u003C\/span\u003E9 October 2004.\u003C\/li\u003E\u003Cli xmlns:hwp=\u0022http:\/\/schema.highwire.org\/Journal\u0022 class=\u0022accepted\u0022 hwp:start=\u00222004-11-15\u0022\u003E\u003Cspan class=\u0022accepted-label\u0022\u003EAccepted \u003C\/span\u003E15 November 2004.\u003C\/li\u003E\u003C\/ul\u003E\u003Cli class=\u0022fn fn-group-article-title\u0022 id=\u0022fn-1\u0022\u003E\u003Cp id=\u0022p-42\u0022\u003E\u003Ca class=\u0022rev-xref\u0022 href=\u0022#xref-fn-1-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cspan class=\u0022fn-label\u0022\u003E\u2020\u003C\/span\u003E Supplemental material for this article may be found at \u003Ca href=\u0022http:\/\/jb.asm.org\/\u0022\u003Ehttp:\/\/jb.asm.org\/\u003C\/a\u003E.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003EAmerican Society for Microbiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section ref-list\u0022 id=\u0022ref-list-1\u0022\u003E\u003Ch2 class=\u0022\u0022\u003EREFERENCES\u003C\/h2\u003E\u003Col class=\u0022cit-list\u0022\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-1-1\u0022 title=\u0022View reference 1 in text\u0022 id=\u0022ref-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.1\u0022 data-doi=\u002210.1101\/gad.7.1.139\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EBai, U., I. 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Z. Rudner, and R. Losick.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2003\u003C\/span\u003E. RacA, a bacterial protein that anchors chromosomes to the cell poles. \u003Cspan class=\u0022cit-source\u0022\u003EScience\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E299\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E532\u003C\/span\u003E-536.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1079914%26rft_id%253Dinfo%253Apmid%252F12493822%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIyOTkvNTYwNi81MzIiO3M6NDoiYXRvbSI7czoxOToiL2piLzE4Ny80LzEzNTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-3-1\u0022 title=\u0022View reference 3 in text\u0022 id=\u0022ref-3\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.3\u0022 data-doi=\u002210.1073\/pnas.191384198\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EBranda, S. S., J. E. Gonzalez-Pastor, S. Ben-Yehuda, R. Losick, and R. Kolter.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2001\u003C\/span\u003E. Fruiting body formation by \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EProc. Natl. Acad. Sci. 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S., J. E. Gonzalez-Pastor, E. Dervyn, S. D. Ehrlich, R. Losick, and R. Kolter.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2004\u003C\/span\u003E. Genes involved in formation of structured multicellular communities by \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJ. 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A., P. Eichenberger, J. E. Gonzalez-Pastor, P. Fawcett, R. Monson, R. Losick, and A. D. Grossman.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2002\u003C\/span\u003E. Genome-wide analysis of the stationary-phase sigma factor (sigma-H) regulon of \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJ. Bacteriol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E184\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E4881\u003C\/span\u003E-4890.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2BBacteriology%26rft.stitle%253DJ.%2BBacteriol.%26rft.aulast%253DBritton%26rft.auinit1%253DR.%2BA.%26rft.volume%253D184%26rft.issue%253D17%26rft.spage%253D4881%26rft.epage%253D4890%26rft.atitle%253DGenome-Wide%2BAnalysis%2Bof%2Bthe%2BStationary-Phase%2BSigma%2BFactor%2B%2528Sigma-H%2529%2BRegulon%2Bof%2BBacillus%2Bsubtilis%26rft_id%253Dinfo%253Adoi%252F10.1128%252FJB.184.17.4881-4890.2002%26rft_id%253Dinfo%253Apmid%252F12169614%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MjoiamIiO3M6NToicmVzaWQiO3M6MTE6IjE4NC8xNy80ODgxIjtzOjQ6ImF0b20iO3M6MTk6Ii9qYi8xODcvNC8xMzU3LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-6-1\u0022 title=\u0022View reference 6 in text\u0022 id=\u0022ref-6\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.6\u0022 data-doi=\u002210.1016\/0092-8674(91)90238-T\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EBurbulys, D., K. A. Trach, and J. A. Hoch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1991\u003C\/span\u003E. Initiation of sporulation in \u003Cem\u003EB. subtilis\u003C\/em\u003E is controlled by a multicomponent phosphorelay. \u003Cspan class=\u0022cit-source\u0022\u003ECell\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E64\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E545\u003C\/span\u003E-552.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DCell%26rft.stitle%253DCell%26rft.aulast%253DBurbulys%26rft.auinit1%253DD.%26rft.volume%253D64%26rft.issue%253D3%26rft.spage%253D545%26rft.epage%253D552%26rft.atitle%253DInitiation%2Bof%2Bsporulation%2Bin%2BB.%2Bsubtilis%2Bis%2Bcontrolled%2Bby%2Ba%2Bmulticomponent%2Bphosphorelay.%26rft_id%253Dinfo%253Adoi%252F10.1016%252F0092-8674%252891%252990238-T%26rft_id%253Dinfo%253Apmid%252F1846779%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/0092-8674(91)90238-T\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=1846779\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1991EX36100010\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-7-1\u0022 title=\u0022View reference 7 in text\u0022 id=\u0022ref-7\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.7\u0022 data-doi=\u002210.1016\/0076-6879(91)08010-F\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003ECarey, J.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1991\u003C\/span\u003E. Gel retardation. \u003Cspan class=\u0022cit-source\u0022\u003EMethods Enzymol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E208\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E103\u003C\/span\u003E-117.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMethods%2Bin%2Benzymology%26rft.stitle%253DMethods%2BEnzymol%26rft.aulast%253DCarey%26rft.auinit1%253DJ.%26rft.volume%253D208%26rft.spage%253D103%26rft.epage%253D117%26rft.atitle%253DGel%2Bretardation.%26rft_id%253Dinfo%253Adoi%252F10.1016%252F0076-6879%252891%252908010-F%26rft_id%253Dinfo%253Apmid%252F1779832%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/0076-6879(91)08010-F\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=1779832\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1991MC42800009\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-8-1\u0022 title=\u0022View reference 8 in text\u0022 id=\u0022ref-8\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.8\u0022 data-doi=\u002210.1128\/jb.173.8.2625-2632.1991\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EChibazakura, T., F. Kawamura, and H. Takahashi.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1991\u003C\/span\u003E. Differential regulation of \u003Cem\u003Espo0A\u003C\/em\u003E transcription in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E: glucose represses promoter switching at the initiation of sporulation. \u003Cspan class=\u0022cit-source\u0022\u003EJ. Bacteriol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E173\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E2625\u003C\/span\u003E-2632.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2BBacteriology%26rft.stitle%253DJ.%2BBacteriol.%26rft.aulast%253DChibazakura%26rft.auinit1%253DT.%26rft.volume%253D173%26rft.issue%253D8%26rft.spage%253D2625%26rft.epage%253D2632%26rft.atitle%253DDifferential%2Bregulation%2Bof%2Bspo0A%2Btranscription%2Bin%2BBacillus%2Bsubtilis%253A%2Bglucose%2Brepresses%2Bpromoter%2Bswitching%2Bat%2Bthe%2Binitiation%2Bof%2Bsporulation.%26rft_id%253Dinfo%253Adoi%252F10.1128%252Fjb.173.8.2625-2632.1991%26rft_id%253Dinfo%253Apmid%252F1901572%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MjoiamIiO3M6NToicmVzaWQiO3M6MTA6IjE3My84LzI2MjUiO3M6NDoiYXRvbSI7czoxOToiL2piLzE4Ny80LzEzNTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-9-1\u0022 title=\u0022View reference 9 in text\u0022 id=\u0022ref-9\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.9\u0022 data-doi=\u002210.1128\/jb.176.7.1977-1984.1994\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EChung, J. D., G. Stephanopoulos, K. Ireton, and A. D. Grossman.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1994\u003C\/span\u003E. Gene expression in single cells of \u003Cem\u003EBacillus subtilis\u003C\/em\u003E: evidence that a threshold mechanism controls the initiation of sporulation. \u003Cspan class=\u0022cit-source\u0022\u003EJ. Bacteriol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E176\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E1977\u003C\/span\u003E-1984.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2BBacteriology%26rft.stitle%253DJ.%2BBacteriol.%26rft.aulast%253DChung%26rft.auinit1%253DJ.%2BD.%26rft.volume%253D176%26rft.issue%253D7%26rft.spage%253D1977%26rft.epage%253D1984%26rft.atitle%253DGene%2Bexpression%2Bin%2Bsingle%2Bcells%2Bof%2BBacillus%2Bsubtilis%253A%2Bevidence%2Bthat%2Ba%2Bthreshold%2Bmechanism%2Bcontrols%2Bthe%2Binitiation%2Bof%2Bsporulation.%26rft_id%253Dinfo%253Adoi%252F10.1128%252Fjb.176.7.1977-1984.1994%26rft_id%253Dinfo%253Apmid%252F8144465%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MjoiamIiO3M6NToicmVzaWQiO3M6MTA6IjE3Ni83LzE5NzciO3M6NDoiYXRvbSI7czoxOToiL2piLzE4Ny80LzEzNTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-10-1\u0022 title=\u0022View reference 10 in text\u0022 id=\u0022ref-10\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.10\u0022 data-doi=\u002210.1073\/pnas.140209597\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EFawcett, P., P. Eichenberger, R. Losick, and P. Youngman.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2000\u003C\/span\u003E. The transcriptional profile of early to middle sporulation in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EProc. Natl. Acad. Sci. USA\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E97\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E8063\u003C\/span\u003E-8068.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BUSA%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.140209597%26rft_id%253Dinfo%253Apmid%252F10869437%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMDoiOTcvMTQvODA2MyI7czo0OiJhdG9tIjtzOjE5OiIvamIvMTg3LzQvMTM1Ny5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-11-1\u0022 title=\u0022View reference 11 in text\u0022 id=\u0022ref-11\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.11\u0022 data-doi=\u002210.1046\/j.1365-2443.2000.00307.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EFujita, M.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2000\u003C\/span\u003E. Temporal and selective association of multiple sigma factors with RNA polymerase during sporulation in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EGenes Cells\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E5\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E79\u003C\/span\u003E-88.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DGenes%2Bto%2BCells%26rft.stitle%253DGENES%2BCELLS%26rft.aulast%253DFujita%26rft.auinit1%253DM%26rft.volume%253D5%26rft.issue%253D2%26rft.spage%253D79%26rft.epage%253D88%26rft.atitle%253DTemporal%2Band%2Bselective%2Bassociation%2Bof%2Bmultiple%2Bsigma%2Bfactors%2Bwith%2BRNA%2Bpolymerase%2Bduring%2Bsporulation%2Bin%2BBacillus%2Bsubtilis%26rft_id%253Dinfo%253Adoi%252F10.1046%252Fj.1365-2443.2000.00307.x%26rft_id%253Dinfo%253Apmid%252F10672039%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1046\/j.1365-2443.2000.00307.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10672039\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000086318500001\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-12-1\u0022 title=\u0022View reference 12 in text\u0022 id=\u0022ref-12\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.12\u0022 data-doi=\u002210.1046\/j.1365-2958.2002.02732.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EFujita, M., and R. Losick.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2002\u003C\/span\u003E. An investigation into the compartmentalization of the sporulation transcription factor \u03c3\u003Csup\u003EE\u003C\/sup\u003E in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E43\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E27\u003C\/span\u003E-38.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DFujita%26rft.auinit1%253DM.%26rft.volume%253D43%26rft.issue%253D1%26rft.spage%253D27%26rft.epage%253D38%26rft.atitle%253DAn%2Binvestigation%2Binto%2Bthe%2Bcompartmentalization%2Bof%2Bthe%2Bsporulation%2Btranscription%2Bfactor%2BsigmaE%2Bin%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1046%252Fj.1365-2958.2002.02732.x%26rft_id%253Dinfo%253Apmid%252F11849534%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1046\/j.1365-2958.2002.02732.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=11849534\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000173959400003\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-13-1\u0022 title=\u0022View reference 13 in text\u0022 id=\u0022ref-13\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.13\u0022 data-doi=\u002210.1101\/gad.1078303\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EFujita, M., and R. 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Cannibalism by sporulating bacteria. \u003Cspan class=\u0022cit-source\u0022\u003EScience\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E301\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E510\u003C\/span\u003E-513.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1086462%26rft_id%253Dinfo%253Apmid%252F12817086%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzMDEvNTYzMi81MTAiO3M6NDoiYXRvbSI7czoxOToiL2piLzE4Ny80LzEzNTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-17-1\u0022 title=\u0022View reference 17 in text\u0022 id=\u0022ref-17\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.17\u0022 data-doi=\u002210.1146\/annurev.ge.29.120195.002401\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EGrossman, A. 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Genet.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E29\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E477\u003C\/span\u003E-508.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DAnnual%2Breview%2Bof%2Bgenetics%26rft.stitle%253DAnnu%2BRev%2BGenet%26rft.aulast%253DGrossman%26rft.auinit1%253DA.%2BD.%26rft.volume%253D29%26rft.issue%253D1%26rft.spage%253D477%26rft.epage%253D508%26rft.atitle%253DGenetic%2BNetworks%2BControlling%2Bthe%2BInitiation%2Bof%2BSporulation%2Band%2Bthe%2BDevelopment%2Bof%2BGenetic%2BCompetence%2Bin%2BBacillus%2Bsubtilis%26rft_id%253Dinfo%253Adoi%252F10.1146%252Fannurev.ge.29.120195.002401%26rft_id%253Dinfo%253Apmid%252F8825484%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1146\/annurev.ge.29.120195.002401\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=8825484\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1995TL71900019\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-18-1\u0022 title=\u0022View reference 18 in text\u0022 id=\u0022ref-18\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.18\u0022 data-doi=\u002210.1016\/S0378-1119(96)00404-0\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EGuerout-Fleury, A. M., N. Frandsen, and P. Stragier.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1996\u003C\/span\u003E. Plasmids for ectopic integration in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EGene\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E180\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E57\u003C\/span\u003E-61.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DGene%26rft.stitle%253DGene%26rft.aulast%253DGu%25C3%25A9rout-Fleury%26rft.auinit1%253DA.%2BM.%26rft.volume%253D180%26rft.issue%253D1-2%26rft.spage%253D57%26rft.epage%253D61%26rft.atitle%253DPlasmids%2Bfor%2Bectopic%2Bintegration%2Bin%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0378-1119%252896%252900404-0%26rft_id%253Dinfo%253Apmid%252F8973347%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/S0378-1119(96)00404-0\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=8973347\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1996VY05400009\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-19-1\u0022 title=\u0022View reference 19 in text\u0022 id=\u0022ref-19\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.19\u0022 data-doi=\u002210.1046\/j.1365-2958.2001.02709.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EHamon, M. A., and B. A. Lazazzera.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2001\u003C\/span\u003E. The sporulation transcription factor Spo0A is required for biofilm development in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E42\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E1199\u003C\/span\u003E-1209.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DHamon%26rft.auinit1%253DM.%2BA.%26rft.volume%253D42%26rft.issue%253D5%26rft.spage%253D1199%26rft.epage%253D1209%26rft.atitle%253DThe%2Bsporulation%2Btranscription%2Bfactor%2BSpo0A%2Bis%2Brequired%2Bfor%2Bbiofilm%2Bdevelopment%2Bin%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1046%252Fj.1365-2958.2001.02709.x%26rft_id%253Dinfo%253Apmid%252F11886552%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1046\/j.1365-2958.2001.02709.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=11886552\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000172812700005\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-20-1\u0022 title=\u0022View reference 20 in text\u0022 id=\u0022ref-20\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.20\u0022 data-doi=\u002210.1111\/j.1365-2958.2004.04023.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EHamon, M. A., N. R. Stanley, R. A. Britton, A. D. Grossman, and B. A. Lazazzera.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2004\u003C\/span\u003E. Identification of AbrB-regulated genes involved in biofilm formation by \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E52\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E847\u003C\/span\u003E-860.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DHamon%26rft.auinit1%253DM.%2BA.%26rft.volume%253D52%26rft.issue%253D3%26rft.spage%253D847%26rft.epage%253D860%26rft.atitle%253DIdentification%2Bof%2BAbrB-regulated%2Bgenes%2Binvolved%2Bin%2Bbiofilm%2Bformation%2Bby%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1365-2958.2004.04023.x%26rft_id%253Dinfo%253Apmid%252F15101989%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1111\/j.1365-2958.2004.04023.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=15101989\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000220941400021\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-21-1\u0022 title=\u0022View reference 21 in text\u0022 id=\u0022ref-21\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.21\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EHoch, J. A.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1991\u003C\/span\u003E. \u003Cem\u003Espo0\u003C\/em\u003E genes, the phosphorelay, and the initiation of sporulation, p. \u003Cspan class=\u0022cit-fpage\u0022\u003E747\u003C\/span\u003E-755. \u003Cem\u003EIn\u003C\/em\u003E A. L. Sonenshein, J. A. Hoch, and R. Losick (ed.), \u003Cspan class=\u0022cit-source\u0022\u003E\u003Cem\u003EBacillus subtilis\u003C\/em\u003E and other gram-positive bacteria: biochemistry, physiology, and molecular genetics\u003C\/span\u003E. American Society for Microbiology, Washington, D.C.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-22-1\u0022 title=\u0022View reference 22 in text\u0022 id=\u0022ref-22\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.22\u0022 data-doi=\u002210.1111\/j.1365-2958.2004.03996.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EKearns, D. B., F. Chu, S. S. Branda, R. Kolter, and R. Losick.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2004\u003C\/span\u003E. A master regulator for biofilm formation by \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E52\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E357\u003C\/span\u003E-369.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DKearns%26rft.auinit1%253DD.%2BB.%26rft.volume%253D52%26rft.issue%253D2%26rft.spage%253D357%26rft.epage%253D369%26rft.atitle%253DGenes%2Bgoverning%2Bswarming%2Bin%2BBacillus%2Bsubtilis%2Band%2Bevidence%2Bfor%2Ba%2Bphase%2Bvariation%2Bmechanism%2Bcontrolling%2Bsurface%2Bmotility.%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1365-2958.2004.03996.x%26rft_id%253Dinfo%253Apmid%252F15066026%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1111\/j.1365-2958.2004.03996.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=15066026\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000220624000005\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-23-1\u0022 title=\u0022View reference 23 in text\u0022 id=\u0022ref-23\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.23\u0022 data-doi=\u002210.1046\/j.1365-2958.2003.03818.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EMolle, V., M. Fujita, S. T. Jensen, P. Eichenberger, J. E. Gonzalez-Pastor, J. S. Liu, and R. Losick.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2003\u003C\/span\u003E. The Spo0A regulon of \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E50\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E1683\u003C\/span\u003E-1701.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DMolle%26rft.auinit1%253DV.%26rft.volume%253D50%26rft.issue%253D5%26rft.spage%253D1683%26rft.epage%253D1701%26rft.atitle%253DThe%2BSpo0A%2Bregulon%2Bof%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1046%252Fj.1365-2958.2003.03818.x%26rft_id%253Dinfo%253Apmid%252F14651647%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1046\/j.1365-2958.2003.03818.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=14651647\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000186698600018\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-24-1\u0022 title=\u0022View reference 24 in text\u0022 id=\u0022ref-24\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.24\u0022 data-doi=\u002210.1016\/0092-8674(94)90035-3\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EPerego, M., C. Hanstein, K. M. Welsh, T. Djavakhishvili, P. Glaser, and J. A. Hoch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1994\u003C\/span\u003E. Multiple protein-aspartate phosphatases provide a mechanism for the integration of diverse signals in the control of development in \u003Cem\u003EB. subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003ECell\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E79\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E1047\u003C\/span\u003E-1055.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DCell%26rft.stitle%253DCell%26rft.aulast%253DPerego%26rft.auinit1%253DM.%26rft.volume%253D79%26rft.issue%253D6%26rft.spage%253D1047%26rft.epage%253D1055%26rft.atitle%253DMultiple%2Bprotein-aspartate%2Bphosphatases%2Bprovide%2Ba%2Bmechanism%2Bfor%2Bthe%2Bintegration%2Bof%2Bdiverse%2Bsignals%2Bin%2Bthe%2Bcontrol%2Bof%2Bdevelopment%2Bin%2BB.%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1016%252F0092-8674%252894%252990035-3%26rft_id%253Dinfo%253Apmid%252F8001132%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/0092-8674(94)90035-3\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=8001132\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1994PY08600014\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-25-1\u0022 title=\u0022View reference 25 in text\u0022 id=\u0022ref-25\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.25\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EPerego, M., and J. A. Hoch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2002\u003C\/span\u003E. Two-component systems, phosphorelays, and regulation of their activities by phosphatases, p. \u003Cspan class=\u0022cit-fpage\u0022\u003E473\u003C\/span\u003E-481. \u003Cem\u003EIn\u003C\/em\u003E A. L. Sonenshein, J. A. Hoch, and R. Losick (ed.), \u003Cspan class=\u0022cit-source\u0022\u003E\u003Cem\u003EBacillus subtilis\u003C\/em\u003E and its closest relatives: from genes to cells\u003C\/span\u003E. American Society for Microbiology, Washington, D.C.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-26-1\u0022 title=\u0022View reference 26 in text\u0022 id=\u0022ref-26\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.26\u0022 data-doi=\u002210.1111\/j.1365-2958.1988.tb00079.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EPerego, M., G. B. Spiegelman, and J. A. Hoch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1988\u003C\/span\u003E. Structure of the gene for the transition state regulator, \u003Cem\u003EabrB\u003C\/em\u003E: regulator synthesis is controlled by the \u003Cem\u003Espo0A\u003C\/em\u003E sporulation gene in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E2\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E689\u003C\/span\u003E-699.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DPerego%26rft.auinit1%253DM.%26rft.volume%253D2%26rft.issue%253D6%26rft.spage%253D689%26rft.epage%253D699%26rft.atitle%253DStructure%2Bof%2Bthe%2Bgene%2Bfor%2Bthe%2Btransition%2Bstate%2Bregulator%252C%2BabrB%253A%2Bregulator%2Bsynthesis%2Bis%2Bcontrolled%2Bby%2Bthe%2Bspo0A%2Bsporulation%2Bgene%2Bin%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1365-2958.1988.tb00079.x%26rft_id%253Dinfo%253Apmid%252F3145384%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1111\/j.1365-2958.1988.tb00079.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=3145384\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1988Q831000001\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-27-1\u0022 title=\u0022View reference 27 in text\u0022 id=\u0022ref-27\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.27\u0022 data-doi=\u002210.1007\/s00018-002-8431-9\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EPhillips, Z. E., and M. A. Strauch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2002\u003C\/span\u003E. \u003Cem\u003EBacillus subtilis\u003C\/em\u003E sporulation and stationary phase gene expression. \u003Cspan class=\u0022cit-source\u0022\u003ECell. Mol. Life Sci.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E59\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E392\u003C\/span\u003E-402.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DCellular%2Band%2Bmolecular%2Blife%2Bsciences%2B%253A%2B%2BCMLS%26rft.stitle%253DCell%2BMol%2BLife%2BSci%26rft.aulast%253DPhillips%26rft.auinit1%253DZ.%2BE.%26rft.volume%253D59%26rft.issue%253D3%26rft.spage%253D392%26rft.epage%253D402%26rft.atitle%253DBacillus%2Bsubtilis%2Bsporulation%2Band%2Bstationary%2Bphase%2Bgene%2Bexpression.%26rft_id%253Dinfo%253Adoi%252F10.1007%252Fs00018-002-8431-9%26rft_id%253Dinfo%253Apmid%252F11964117%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1007\/s00018-002-8431-9\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=11964117\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000174840500002\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-28-1\u0022 title=\u0022View reference 28 in text\u0022 id=\u0022ref-28\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.28\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EPiggot, P. 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Smith.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1992\u003C\/span\u003E. \u003Cem\u003EBacillus subtilis\u003C\/em\u003E early sporulation genes \u003Cem\u003EkinA\u003C\/em\u003E, \u003Cem\u003Espo0F\u003C\/em\u003E, and \u003Cem\u003Espo0A\u003C\/em\u003E are transcribed by the RNA polymerase containing \u03c3\u003Csup\u003EH\u003C\/sup\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJ. 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A.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1993\u003C\/span\u003E. AbrB, a transition state regulator, p. \u003Cspan class=\u0022cit-fpage\u0022\u003E757\u003C\/span\u003E-764. \u003Cem\u003EIn\u003C\/em\u003E A. L. Sonenshein, J. A. Hoch, and R. Losick (ed.), \u003Cspan class=\u0022cit-source\u0022\u003E\u003Cem\u003EBacillus subtilis\u003C\/em\u003E and other gram-positive bacteria: biochemistry, physiology, and molecular genetics\u003C\/span\u003E. American Society for Microbiology, Washington, D.C.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-35-1\u0022 title=\u0022View reference 35 in text\u0022 id=\u0022ref-35\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.35\u0022 data-doi=\u002210.1016\/0959-437X(93)90024-J\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EStrauch, M. A., and J. A. Hoch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1993\u003C\/span\u003E. Signal transduction in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E sporulation. \u003Cspan class=\u0022cit-source\u0022\u003ECurr. Opin. Genet. Dev.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E3\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E203\u003C\/span\u003E-212.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DCurrent%2Bopinion%2Bin%2Bgenetics%2B%2526%2Bdevelopment%26rft.stitle%253DCurr%2BOpin%2BGenet%2BDev%26rft.aulast%253DStrauch%26rft.auinit1%253DM.%2BA.%26rft.volume%253D3%26rft.issue%253D2%26rft.spage%253D203%26rft.epage%253D212%26rft.atitle%253DSignal%2Btransduction%2Bin%2BBacillus%2Bsubtilis%2Bsporulation.%26rft_id%253Dinfo%253Adoi%252F10.1016%252F0959-437X%252893%252990024-J%26rft_id%253Dinfo%253Apmid%252F8504245%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1016\/0959-437X(93)90024-J\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=8504245\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-36-1\u0022 title=\u0022View reference 36 in text\u0022 id=\u0022ref-36\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.36\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EStrauch, M. A., G. B. Spiegelman, M. Perego, W. C. Johnson, D. Burbulys, and J. A. Hoch.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1989\u003C\/span\u003E. The transition state transcription regulator \u003Cem\u003EabrB\u003C\/em\u003E of \u003Cem\u003EBacillus subtilis\u003C\/em\u003E is a DNA binding protein. \u003Cspan class=\u0022cit-source\u0022\u003EEMBO J.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E8\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E1615\u003C\/span\u003E-1621.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DThe%2BEMBO%2BJournal%26rft.stitle%253DEMBO%2BJournal%26rft.aulast%253DStrauch%26rft.auinit1%253DM.%26rft.volume%253D8%26rft.issue%253D5%26rft.spage%253D1615%26rft.epage%253D1621%26rft.atitle%253DThe%2Btransition%2Bstate%2Btranscription%2Bregulator%2BabrB%2Bof%2BBacillus%2Bsubtilis%2Bis%2Ba%2BDNA%2Bbinding%2Bprotein%26rft_id%253Dinfo%253Apmid%252F2504584%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=2504584\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=A1989U504800039\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-37-1\u0022 title=\u0022View reference 37 in text\u0022 id=\u0022ref-37\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.37\u0022 data-doi=\u002210.1046\/j.1365-2958.2003.03643.x\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EWu, L. J., and J. Errington.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E2003\u003C\/span\u003E. RacA and the Soj-Spo0J system combine to effect polar chromosome segregation in sporulating \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EMol. Microbiol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E49\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E1463\u003C\/span\u003E-1475.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DMolecular%2Bmicrobiology%26rft.stitle%253DMol%2BMicrobiol%26rft.aulast%253DWu%26rft.auinit1%253DL.%2BJ.%26rft.volume%253D49%26rft.issue%253D6%26rft.spage%253D1463%26rft.epage%253D1475%26rft.atitle%253DRacA%2Band%2Bthe%2BSoj-Spo0J%2Bsystem%2Bcombine%2Bto%2Beffect%2Bpolar%2Bchromosome%2Bsegregation%2Bin%2Bsporulating%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1046%252Fj.1365-2958.2003.03643.x%26rft_id%253Dinfo%253Apmid%252F12950914%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=10.1046\/j.1365-2958.2003.03643.x\u0026amp;link_type=DOI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref\u0022\u003E\u003Cspan\u003ECrossRef\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=12950914\u0026amp;link_type=MED\u0026amp;atom=%2Fjb%2F187%2F4%2F1357.atom\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-medline\u0022\u003E\u003Cspan\u003EPubMed\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/external-ref?access_num=000185190700002\u0026amp;link_type=ISI\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-newisilink cit-ref-sprinkles-webofscience\u0022\u003E\u003Cspan\u003EWeb of Science\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-38-1\u0022 title=\u0022View reference 38 in text\u0022 id=\u0022ref-38\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.38\u0022 data-doi=\u002210.1073\/pnas.80.8.2305\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EYoungman, P. J., J. B. Perkins, and R. Losick.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1983\u003C\/span\u003E. Genetic transposition and insertional mutagenesis in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E with \u003Cem\u003EStreptococcus faecalis\u003C\/em\u003E transposon Tn\u003Cem\u003E917\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EProc. Natl. Acad. Sci. USA\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E80\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E2305\u003C\/span\u003E-2309.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DPNAS%26rft.stitle%253DProc.%2BNatl.%2BAcad.%2BSci.%2BUSA%26rft.aulast%253DYoungman%26rft.auinit1%253DP.%2BJ.%26rft.volume%253D80%26rft.issue%253D8%26rft.spage%253D2305%26rft.epage%253D2309%26rft.atitle%253DGenetic%2Btransposition%2Band%2Binsertional%2Bmutagenesis%2Bin%2BBacillus%2Bsubtilis%2Bwith%2BStreptococcus%2Bfaecalis%2Btransposon%2BTn917.%26rft_id%253Dinfo%253Adoi%252F10.1073%252Fpnas.80.8.2305%26rft_id%253Dinfo%253Apmid%252F6300908%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czo5OiI4MC84LzIzMDUiO3M6NDoiYXRvbSI7czoxOToiL2piLzE4Ny80LzEzNTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-39-1\u0022 title=\u0022View reference 39 in text\u0022 id=\u0022ref-39\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-187.4.1357.39\u0022 data-doi=\u002210.1128\/jb.169.5.2223-2230.1987\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Ccite\u003E\u003Cstrong\u003EZuber, P., and R. Losick.\u003C\/strong\u003E \u003Cspan class=\u0022cit-pub-date\u0022\u003E1987\u003C\/span\u003E. Role of AbrB in Spo0A- and Spo0B-dependent utilization of a sporulation promoter in \u003Cem\u003EBacillus subtilis\u003C\/em\u003E. \u003Cspan class=\u0022cit-source\u0022\u003EJ. Bacteriol.\u003C\/span\u003E \u003Cspan class=\u0022cit-vol\u0022\u003E169\u003C\/span\u003E\u003Cstrong\u003E:\u003C\/strong\u003E\u003Cspan class=\u0022cit-fpage\u0022\u003E2223\u003C\/span\u003E-2230.\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DJournal%2Bof%2BBacteriology%26rft.stitle%253DJ.%2BBacteriol.%26rft.aulast%253DZuber%26rft.auinit1%253DP.%26rft.volume%253D169%26rft.issue%253D5%26rft.spage%253D2223%26rft.epage%253D2230%26rft.atitle%253DRole%2Bof%2BAbrB%2Bin%2BSpo0A-%2Band%2BSpo0B-dependent%2Butilization%2Bof%2Ba%2Bsporulation%2Bpromoter%2Bin%2BBacillus%2Bsubtilis.%26rft_id%253Dinfo%253Adoi%252F10.1128%252Fjb.169.5.2223-2230.1987%26rft_id%253Dinfo%253Apmid%252F2437099%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MjoiamIiO3M6NToicmVzaWQiO3M6MTA6IjE2OS81LzIyMjMiO3M6NDoiYXRvbSI7czoxOToiL2piLzE4Ny80LzEzNTcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003C\/div\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022https:\/\/jb.asm.org\/content\/187\/4\/1357.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Abstract\u003C\/a\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022https:\/\/jb.asm.org\/sites\/default\/files\/js\/js_B0g9oatDRbugYOCQxVjw-T7D6Bi_uIh2_7aHA5rl89U.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}